Inhibitors of hepatitis C virus

ABSTRACT

A class of compounds that inhibit Hepatitis C Virus (HCV) is disclosed, along with compositions containing the compound, and methods of using the composition for treating individuals infected with HCV.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/544,261, filed Jul. 9, 2012, now U.S. Pat. No. 8,614,207 which is aby-pass continuation application under 35 U.S.C. §111 (a) ofInternational Patent Application No. PCT/US2011/057398, filed Oct. 21,2011, which claims the benefit of priority to U.S. ProvisionalApplication No. 61/524,220, filed Aug. 16, 2011; U.S. ProvisionalApplication No. 61/438,429, filed Feb. 1, 2011; and U.S. ProvisionalApplication No. 61/406,972, filed Oct. 26, 2010. Each of these priorapplications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to compounds useful for inhibiting hepatitis Cvirus (“HCV”) replication, particularly functions of the non-structural5B (“NS5B”) protein of HCV.

BACKGROUND OF THE INVENTION

HCV is a single-stranded RNA virus that is a member of the Flaviviridaefamily. The virus shows extensive genetic heterogeneity as there arecurrently seven identified genotypes and more than 50 identifiedsubtypes. In HCV infected cells, viral RNA is translated into apolyprotein that is cleaved into ten individual proteins. At the aminoterminus are structural proteins: the core (C) protein and the envelopeglycoproteins, E1 and E2. p7, an integral membrane protein, follows E1and E2. Additionally, there are six non-structural proteins, NS2, NS3,NS4A, NS4B, NS5A and NS5B, which play a functional role in the HCV lifecycle. (see, for example, B. D. Lindenbach and C. M. Rice, Nature.436:933-938, 2005). NS5B is the RNA polymerase or replicase of the virusand is responsible for replication of both positive and negative-strandgenomic RNA during the viral replicative cycle. NS5B plays an essentialand critical role in viral replication, and a functional NS5B replicaseis required for HCV replication and infection. Thus, inhibition of NS5BRNA-dependent polymerase activity is believed to be an effective way oftreating HCV infection.

Infection by HCV is a serious health issue. It is estimated that 170million people worldwide are chronically infected with HCV. HCVinfection can lead to chronic hepatitis, cirrhosis, liver failure andhepatocellular carcinoma. Chronic HCV infection is thus a majorworldwide cause of liver-related premature mortality.

The current standard of care treatment regimen for HCV infectioninvolves interferon-alpha, alone, or in combination with ribavirin and aprotease inhibitor. The treatment is cumbersome and sometimes hasdebilitating and severe side effects and many patients do not durablyrespond to treatment. New and effective methods of treating HCVinfection are urgently needed.

SUMMARY OF THE INVENTION

Essential functions of the NS5B protein in HCV replication make it anattractive intervention target for treating HCV infection. The presentdisclosure describes a class of compounds targeting the NS5B protein andmethods of their use to treat HCV infection in humans.

The present disclosure describes a class of heterocyclic compoundstargeting HCV NS5B polymerase and methods of their use to treat HCVinfection in humans.

In a first aspect of the invention, compounds of formula I are provided:

wherein,

-   L¹, L² and L³ together with the attached carbons of the aromatic    ring form a 5-12 member ring containing 0-4 heteroatoms selected    from the group consisting of N, O, S, P and/or Si;-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   U and V are each independently CH, N, CF, CCl, or CCN;-   W, X, and Z are each independently C or N;-   Y is selected from NR^(N), N, O, S, Se, and —CR^(a)R^(b);-   R^(N) is selected from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₄₋₅    heterocycle, aryl, heteroaryl, amide, sulfonamide, and carbamate;-   R^(a), R^(b) are each independently hydrogen, methyl, or together    form a C₃₋₆ cycloalkyl bearing 0-1 heteroatom that is O or NR³;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyl,    cyclopropyl, C₁₋₄ alkoxy, or cyclopropoxy; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy, or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    form a 3-6 member ring optionally containing 0-3 heteroatoms    selected from O, NR^(N) and/or S.

The compounds may have an inhibitory activity with respect to HCV, asmeasured by the concentration of the compound effective to produce ahalf-maximal inhibition of HCV1b replication (EC₅₀) in a1b_Huh-Luc/Neo-ET cell line in culture, of 1 mM or less.

The compounds may have the structure wherein

together with the attached carbons of the aromatic ring, is a seven- oreight-member ring.

The compounds may have the structure wherein

together with the attached carbons of the aromatic ring, form a 5-9member ring, L¹ is —C(R¹⁵R¹⁶)—, and L³ is —N(SO₂Me)- or —O—, where R¹⁵and R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or cyclopropoxy orR¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄ alkenylidene or R¹⁵ and R¹⁶joined together with the attached carbon form a 3-6 member ringoptionally containing 0-3 heteroatoms of O, NR^(N) and/or S.

In a first embodiment of the first aspect,

is selected from the group consisting of

wherein,

-   L¹, L² and L³ together with the attached carbons of the aromatic    ring form a 5-12 member ring containing 0-4 heteroatoms of N, O, S,    P and/or Si;-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy; and-   R¹⁵ and R¹⁶ are each independently selected from hydrogen, hydroxyl,    azide, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄    alkoxy, or cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or    C₁₋₄ alkenylidene or R¹⁵ and R¹⁶ joined together with the attached    carbon form a 3-6 member ring optionally containing 0-3 heteroatoms    of O, NR^(N) and/or S.

In a second embodiment of the first aspect,

is selected from the group consisting of

wherein,

-   L¹, L² and L³ together with the attached carbons of the aromatic    ring form a 5-9 member ring containing 0-4 heteroatoms selected from    N, O, S, P and/or Si;-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹,-   —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy; and-   R¹⁵ and R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member rings optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S.

In a third embodiment of the first aspect, R¹ is hydrogen, halide,—C(O)OR⁶—, —C(O)NHR⁷, —C(═NR⁷)OMe, —C(O)N(OH)R⁷, —C(═NOMe)NHR⁷,C(═NOH)NHR⁷, —CH(CF₃)NHR⁸, —CH(CN)NHR⁹,

wherein,

-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl; and-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from hydrogen,    C₁₋₄ alkyls, cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy.

In a fourth embodiment of the first aspect, R¹ is hydrogen, Br, I,—COOH, —C(O)OMe, —C(O)OEt, —C(O)OtBu, —C(O)NHMe, —C(O)NHOMe,—C(═NOMe)NHMe, —C(═NOH)NHMe, —C(═NMe)OMe, —C(O)N(OH)Me, —C(O)NHS(O)₂Me,—CH(CF₃)NHMe, —CH(CN)NHMe, —C(═NCN)NHMe,

In a fifth embodiment of the first aspect, R¹ is —C(O)NHMe or

In a sixth embodiment of the first aspect, R² is selected from the groupconsisting of

wherein

-   each phenyl moiety is optionally substituted with 0-2 nitrogen    atoms;-   R¹² is selected from the group consisting of hydrogen, halide, —CN,    —OCHF₂, —OCF₃, alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl,    aryloxy, alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl,    sulfonamide, carbamate;-   m is 0, 1, 2, 3, or 4;-   G is O, NR^(N), S, or CR^(a)R^(b);-   A is N, O, S, or CR^(a)R^(b); and-   D, E are each independently C or N.

In a seventh embodiment of the first aspect, R² is selected from thegroup consisting of

wherein,

-   each phenyl moiety is optionally substituted with 0-2 nitrogen    atoms;-   R¹² is selected from the group consisting of hydrogen, halide, —CN,    —OCHF₂, —OCF₃, alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl,    aryloxy, alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl,    sulfonamide, carbamate;-   m is 0, 1, 2, 3, or 4;-   G is O, NR^(N), S, or CR^(a)R^(b);-   A is N, O, S, or CR^(a)R^(b); and-   D, E are each independently C or N.

In an eighth embodiment of the first aspect, R² is selected from thegroup consisting of

wherein, each phenyl moiety is optionally substituted with 0-2 nitrogenatoms.

In a ninth embodiment of the first aspect, R² is

In a tenth embodiment of the first aspect,

is selected from the group consisting

wherein,

-   L¹, L², and L³ are each independently selected from the group    consisting of a bond, —O—, —C(R¹⁵R¹⁶),-   —NR³—, —S(O)_(n)—, —P(O)_(n)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and    substituted alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy,    heterocycle, aryl, heteroaryl, amide, carbamate, urea, and    sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NMe)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹,-   —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy;-   R¹² is C₁₋₃ alkyl, cyclopropyl, —OMe, or —NHMe;-   R¹³ is hydrogen, —Ac, or —S(O)₂Me;-   R¹⁴ is hydrogen or Me;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   A¹ or A² is independently —CR^(a)R^(b)—, —N(R^(N))—, or —O—.

In an eleventh embodiment of the first aspect,

is selected from the group consisting of

wherein,

-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NMe)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy;-   R¹² is C₁₋₃ alkyl, cyclopropyl —OMe, or —NHMe;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   A² is —CR^(a)R^(b)—, —N(R^(N))—, or —O—.

In a twelfth embodiment of the first aspect,

wherein,

-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NMe)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S.

In a second aspect of the invention is a compound that has thestructure:

wherein

-   L¹, L² and —N(SO₂R¹²)— together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group consisting    of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—, —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—,    —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl,    cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea,    and sulfonamide;-   n is 0, 1, or 2; and-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷, —C(CF₃)NHR⁸,    —C(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is an aryl or heteroaryl having one or more R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹² is C₁₋₃ alkyl, cyclopropyl, —OMe, or —NHMe;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is F, Cl or CN.

The compound of this embodiment may have an inhibitory activity withrespect to HCV, as measured by the concentration of the compoundeffective to produce a half-maximal inhibition of HCV1b replication(EC₅₀) in a 1b_Huh-Luc/Neo-ET cell line in culture, of 100 nM or less.

The compound of this embodiment may have the structure in which

is one of

R¹ is selected from the group consisting of

and R² is selected from the group consisting of

The compound in this embodiment may be selected from the groupconsisting of compounds identified by ID NOS: B5, B15, B20, B33, B35,B45, B67, B85, B92, B94, B107, B118, B120, B121, B127, B128, B130, B131,B132, B138, B139, B145, B148, B158, B163, B168, B169, B171, B187, B190,B191, B192, B196, B197, B198, B201, B207, B208, B212, B214, B218, B221,B226, B232, B233, B236, B237, B238, B239, B240, B2, B3, B4, B6, B7, B9,B16, B18, B19, B22, B29, B31, B32, B34, B36, B47, B48, B54, B55, B57,B60, B63, B71, B84, B93, B100, B101, B106, B108, B109, B111, B112, B113,B115, B116, B119, B123, B124, B134, B136, B137, B142, B144, B146, B147,B150, B151, B153, B154, B155, B156, B157, B159, B160, B161, B162, B164,B165, B166, B167, B170, B172, B173, B174, B175, B176, B178, B179, B180,B181, B183, B184, B186, B188, B189, B193, B195, B199, B200, B202, B203,B204, B205, B210, B215, B216, B217, B219, B220, B222, B223, B224, B225,B227, B228, B229, B230, B231, B234, B235, and B241.

In some preferred compounds in this embodiment,

is selected from the group consisting of

The above compounds include compounds identified by ID NOS: B5, B15,B20, B33, B35, B45, B67, B85, B92, B94, B107, B118, B120, B121, B127,B128, B130, B131, B132, B138, B139, B145, B148, B158, B163, B168, B169,B171, B187, B190, B191, B192, B196, B197, B198, B201, B207, B208, B212,B214, B218, B221, B226, B232, B233, B236, B237, B238, B239, and B240.

As can be appreciated, the compounds in this embodiment may besubdivided into subsets wherein

is:

(i) a 7 or 8 member aliphatic ring, as exemplified by compounds B5, B15,B35, B67, B85, B92, B120, B130, B198, B94, and B130;

(ii) a 7 or 8 member ring having an internal oxygen atom, as exemplifiedby compounds B45, B118, B148, B197, B168, B187, B190; B192, B196, B207,B214, B191, B212, B218, B221, B222, B226, B232, B233, B236, B237, B238,B239, and B240;

(iii) a 7 or 8 member ring having a second internal nitrogen atom, asexemplified by compounds B107, B139, B145, B171, and B208; and

(iv) a fused 7 or 8 member ring, as exemplified by compounds B127, B128,B131, B132, B138, B158, B163, B169, B189, and B201.

R¹ in this embodiment may be

The structure

together with the attached carbons of the aromatic ring in thisembodiment may be a seven- or eight-member ring.

R² in this embodiment may be a phenyl substituted with one or more R¹⁷substituents.

R² in this embodiment may be a 4-phenoxyphenyl and the phenoxy group issubstituted with one or more R¹⁷ substituents.

R² in this embodiment may be selected from

In a third aspect of the invention is a compound of formula II

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents,-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a fourth aspect of the invention is a compound that has thestructure:

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring, containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

For the compounds in this embodiment,

may be selected from the group consisting of

R¹ is selected from the group consisting of

and R² is selected from the group consisting of

Exemplary compounds in this embodiment include those identified by IDNOS: B89, B96, B97, B125, B126, and B129.

R¹ in this embodiment may be

R² in this embodiment may be a phenyl substituted with one or more R¹⁷substituents.

R² in this embodiment may be a 4-phenoxyphenyl and the phenoxy group issubstituted with one or more R¹⁷ substituents.

R² in this embodiment may be selected from

In a fifth aspect of the invention is a compound of formula IV

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring, containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

In a sixth aspect of the invention is a compound of formula V

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group consisting    of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—, —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—,    —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl,    cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea,    and sulfonamide;-   n is 0, 1, or 2;-   R^(N) is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₄₋₅ heterocycle,    aryl, heteroaryl, amide, sulfonamide, or carbamate;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a seventh aspect of the invention is a compound of formula VI

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are independently hydrogen, hydroxyl, azide, C₂₋₄ alkenyl,    C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or cyclopropoxy    or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄ alkenylidene or R¹⁵    and R¹⁶ joined together with the attached carbon are 3-6 member ring    optionally containing 0-3 heteroatoms of O, NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In an eighth aspect of the invention is a compound of formula VII

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

In a ninth aspect of the invention is a compound of formula VIII

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents,-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a tenth aspect of the invention is a compound of formula X

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—S(O)_(n)—,    —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl,    alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl,    amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, alkenyl,    C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or cyclopropoxy    or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄ alkenylidene or R¹⁵    and R¹⁶ joined together with the attached carbon are a 3-6 member    ring optionally containing 0-3 heteroatoms of O, NR^(N) and/or S;    and-   R¹⁷ is H, F, Cl or CN.

In an eleventh aspect of the invention is a compound of formula XI

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a twelfth aspect of the invention is a compound of formula XII

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

A thirteenth aspect of the invention provides a pharmaceuticalcomposition comprising the compounds of the invention, including theexemplary compounds identified by the above ID NOS. The composition maybe formulated for oral delivery, and may include a second and/or thirdanti-HCV agent.

Also disclosed is a method of treating HCV infection in a subject by thesteps of administering to the subject, a pharmaceutically acceptabledose of a compound of the invention, and continuing the administeringuntil a selected reduction in the subject's HCV titer is achieved.

The compound administered may be one or more of the exemplary compoundsidentified by the above ID NOS. The method may include administering tothe subject, either in a single or separate administrations, a secondanti-HCV agent selected from the group consisting of interferon-alpha,ribavirin, or both. The administering may be by an oral route.

Also disclosed is a compound as provided herein, for use in thetreatment of HCV infection in an infected subject. The compound may beone of those identified by the ID NOS provided above.

Further disclosed is the use of the above compounds, such as the onesidentified by ID NOS herein, in the preparation of a medicament for thetreatment of HCV in an HCV-infected subject.

Some of the compounds of the invention possess chiral carbons. Theinvention includes all stereoisomeric forms, including enantiomers anddiastereomers as well as mixtures of stereoisomers such as racemates.The stereoisomers or their precursors can be either asymmetricallysynthesized or obtained by separations of the racemates according tomethods commonly known in the art.

The invention is intended to include all isotopically labeled analogs ofthe compounds of the invention. Isotopes include those atoms having thesame atomic number but a different mass. For example, isotopes ofhydrogen include ²H(D) and ³H(T) and isotopes of carbon include ¹³C and¹⁴C. Isotopically labeled compounds of the invention can be preparedaccording to methods commonly known in the art. Such compounds may havevarious potential uses as, but not limited to, standards and reagents indetermining biological/pharmacological activities. For those stableisotopically labeled compounds of the invention, they may have thepotential to favorably modulate biological, pharmacological, orpharmacokinetic properties.

DETAILED DESCRIPTION

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (2007) “Advanced Organic Chemistry 5^(th) Ed.” Vols.A and B, Springer Science+Business Media LLC, New York. The practice ofthe present invention will employ, unless otherwise indicated,conventional methods of synthetic organic chemistry, mass spectroscopy,preparative and analytical methods of chromatography, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology.

The term “alkanoyl” as used herein contemplates a carbonyl group with alower alkyl group as a substituent.

The term “alkenyl” as used herein contemplates substituted orunsubstituted, straight and branched chain alkene radicals, includingboth the E- and Z-forms, containing from two to eight carbon atoms. Thealkenyl group may be optionally substituted with one or moresubstituents selected from the group consisting of halogen, —CN, —NO₂,CO₂R, C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR,—C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, S(O)R, SO₂R, —SO₃R,—S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryland heteroaryl.

The term “alkoxy” as used herein contemplates an oxygen with a loweralkyl group as a substituent and includes methoxy, ethoxy, butoxy,trifluoromethoxy and the like. It also includes divalent substituentslinked to two separated oxygen atoms such as, without limitation,—O—CF₂—O—, —O—(CH₂)₁₋₄—O—(CH₂CH₂—O)₁₋₄— and —(O—CH₂CH₂—O)₁₋₄—.

The term “alkoxycarbonyl” as used herein contemplates a carbonyl groupwith an alkoxy group as a substituent.

The term “alkyl” as used herein contemplates substituted orunsubstituted, straight and branched chain alkyl radicals containingfrom one to fifteen carbon atoms. The term “lower alkyl” as used hereincontemplates both straight and branched chain alkyl radicals containingfrom one to six carbon atoms and includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl and the like. The alkyl group maybe optionally substituted with one or more substituents selected fromhalogen, —CN, —NO₂, —C(O)₂R, —C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R,—N(R^(N))S(O)₂R, —SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR,—SO₂R, —SO₃R, —S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl,cycloalkenyl, aryl and heteroaryl.

The term “alkylene,” “alkenylene” and “alkynylene” as used herein refersto the groups “alkyl,” “alkenyl” and “alkynyl” respectively, when theyare divalent, ie, attached to two atoms.

The term “alkylsulfonyl” as used herein contemplates a sulfonyl groupwhich has a lower alkyl group as a substituent.

The term “alkynyl” as used herein contemplates substituted orunsubstituted, straight and branched carbon chain containing from two toeight carbon atoms and having at least one carbon-carbon triple bond.The term alkynyl includes, for example ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 3-methyl-1-butynyl and the like. The alkynyl group may beoptionally substituted with one or more substituents selected from halo,—CN, —NO₂, —CO₂R, —C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R,—N(R^(N))S(O)₂R, —SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR,—SO₂R, —SO₃R, —S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl,cycloalkenyl, aryl and heteroaryl.

The term “amino” as used herein contemplates a group of the structure—NR^(N) ₂.

The term “amino acid” as used herein contemplates a group of thestructure

in either the D or the L configuration and includes but is not limitedto the twenty “standard” amino acids: isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan, valine, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine and histidine. The present invention alsoincludes, without limitation, D-configuration amino acids, beta-aminoacids, amino acids having side chains as well as all non-natural aminoacids known to one skilled in the art.

The term “aralkyl” as used herein contemplates a lower alkyl group whichhas as a substituent an aromatic group, which aromatic group may besubstituted or unsubstituted. The aralkyl group may be optionallysubstituted with one or more substituents selected from halogen, —CN,—NO₂, —CO₂R, —C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R,—SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —SO₃R,—S(O)₂N(R^(N))₂, phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryland heteroaryl.

The terms “aryl,” “aromatic group” or “aromatic ring” as used hereincontemplates substituted or unsubstituted single-ring and multiplearomatic groups (for example, phenyl, pyridyl and pyrazole, etc.) andpolycyclic ring systems (naphthyl and quinolinyl, etc.). The polycyclicrings may have two or more rings in which two atoms are common to twoadjoining rings (the rings are “fused”) wherein at least one of therings is aromatic, e.g., the other rings can be cycloalkyls,cycloalkenyls, aryl, heterocycles and/or heteroaryls. The aryl group maybe optionally substituted with one or more substituents selected fromhalogen, alkyl, —CN, —NO₂, —CO₂R, —C(O)R, —O—R, —N(R^(N))₂,—N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR, —C(O)N(R^(N))₂, —OC(O)R,—OC(O)N(R^(N))₂, —SOR, —SO₂R, —SO₃R, —S(O)₂N(R^(N))₂, —SiR₃, —P(O)R,phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The term “arylsulfonyl” as used herein contemplates a sulfonyl groupwhich has as a substituent an aryl group. The term is meant to include,without limitation, monovalent as well as multiply valent aryls (eg,divalent aryls).

The term “carbamoyl” as used herein contemplates a group of thestructure

The term “carbonyl” as used herein contemplates a group of the structure

The term “carboxyl” as used herein contemplates a group of the structure

The term “cycloalkyl” as used herein contemplates substituted orunsubstituted cyclic alkyl radicals containing from three to twelvecarbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl and thelike. The term “cycloalkyl” also includes polycyclic systems having tworings in which two or more atoms are common to two adjoining rings (therings are “fused”). The cycloalkyl group may be optionally substitutedwith one or more substituents selected from halo, —CN, —NO₂, —CO₂R,—C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR,—C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —S(O)₂N(R^(N))₂,phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

The term “cycloalkenyl” as used herein contemplates substituted orunsubstituted cyclic alkenyl radicals containing from four to twelvecarbon atoms in which there is at least one double bond between two ofthe ring carbons and includes cyclopentenyl, cyclohexenyl and the like.The term “cycloalkenyl” also includes polycyclic systems having tworings in which two or more atoms are common to two adjoining rings (therings are “fused”). The cycloalkenyl group may be optionally substitutedwith one or more substituents selected from halo, —CN, —NO₂, —CO₂R,—C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R, —N(R^(N))S(O)₂R, —SR,—C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR, —SO₂R, —S(O)₂N(R^(N))₂,phosphate, phosphonate, alkyl, cycloalkenyl, aryl and heteroaryl.

The term “halo” or “halogen” as used herein includes fluorine, chlorine,bromine and iodine.

The term “heteroalkyl” as used herein contemplates an alkyl with one ormore heteroatoms.

The term “heteroatom”, particularly within a ring system, refers to N, Oand S.

The term “heterocyclic group,” “heterocycle” or “heterocyclic ring” asused herein contemplates substituted or unsubstituted aromatic andnon-aromatic cyclic radicals having at least one heteroatom as a ringmember. Preferred heterocyclic groups are those containing five or sixring atoms which includes at least one hetero atom and includes cyclicamines such as morpholino, piperidino, pyrrolidino and the like andcyclic ethers, such as tetrahydrofuran, tetrahydropyran and the like.Aromatic heterocyclic groups, also termed “heteroaryl” groups,contemplates single-ring hetero-aromatic groups that may include fromone to three heteroatoms, for example, pyrrole, furan, thiophene,imidazole, oxazole, thiazole, triazole, pyrazole, oxodiazole,thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine and the like.The term heteroaryl also includes polycyclic hetero-aromatic systemshaving two or more rings in which two or more atoms are common to twoadjoining rings (the rings are “fused”) wherein at least one of therings is a heteroaryl, e.g., the other rings can be cycloalkyls,cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples ofpolycyclic heteroaromatic systems include quinoline, isoquinoline,cinnoline, tetrahydroisoquinoline, quinoxaline, quinazoline,benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,indazole, purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine andthe like. The heterocyclic group may be optionally substituted with oneor more substituents selected from the group consisting of halo, alkyl,—CN, —NO₂, —CO₂R, —C(O)R, —O—R, —N(R^(N))₂, —N(R^(N))C(O)R,—N(R^(N))S(O)₂R, —SR, —C(O)N(R^(N))₂, —OC(O)R, —OC(O)N(R^(N))₂, —SOR,—SO₂R, —SO₃R, —S(O)₂N(R^(N))₂, —SiR₃, —P(O)R, phosphate, phosphonate,cycloalkyl, cycloalkenyl, aryl and heteroaryl.

The term “oxo” as used herein contemplates an oxygen attached with adouble bond.

By “pharmaceutically acceptable” or “pharmacologically acceptable” ismeant a material which is not biologically or otherwise undesirable,i.e., the material may be administered to an individual without causingany undesirable biological effects or interacting in a deleteriousmanner with any of the components of the composition in which it iscontained.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention which is made with counterions understood in the art to begenerally acceptable for pharmaceutical uses and which possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,morpholine, piperidine, dimethylamine, diethylamine and the like. Alsoincluded are salts of amino acids such as arginates and the like, andsalts of organic acids like glucurmic or galactunoric acids and the like(see, e.g., Berge et al., 1977, J. Pharm. Sci. 66:1-19).

The terms “phosphate” and “phosphonate” as used herein refer to themoieties having the following structures, respectively:

The terms “salts” and “hydrates” refers to the hydrated forms of thecompound that would favorably affect the physical or pharmacokineticproperties of the compound, such as solubility, palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which those skilled in the art may take intoaccount in the selection include the cost of the raw materials, ease ofcrystallization, yield, stability, solubility, hygroscopicity,flowability and manufacturability of the resulting bulk drug.

The term sulfonamide as used herein contemplates a group having thestructure

The term “sulfonate” as used herein contemplates a group having thestructure

wherein R^(s) is selected from the group consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkanoyl, or C₁-C₁₀alkoxycarbonyl.

The term “sulfonyl” as used herein contemplates a group having thestructure

“Substituted sulfonyl” as used herein contemplates a group having thestructure

including, but not limited to alkylsulfonyl and arylsulfonyl.

The term “thiocarbonyl,” as used herein, means a carbonyl wherein anoxygen atom has been replaced with a sulfur.

Each R is independently selected from hydrogen, —OH, —CN, —NO₂, halogen,C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide,amino, and oxo.

Each R^(N) is independently selected from the group consisting ofhydrogen, —OH, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate andsulfonamide. Two R^(N) may be taken together with C, O, N or S to whichthey are attached to form a five to seven membered ring which mayoptionally contain a further heteroatom.

The compounds of the present invention may be used to inhibit or reducethe activity of HCV, particularly HCV's NS5B protein. In these contexts,inhibition and reduction of activity of the NS5B protein refers to alower level of the measured activity relative to a control experiment inwhich the cells or the subjects are not treated with the test compound.In particular aspects, the inhibition or reduction in the measuredactivity is at least a 10% reduction or inhibition. One of skill in theart will appreciate that reduction or inhibition of the measuredactivity of at least 20%, 50%, 75%, 90% or 100%, or any number inbetween, may be preferred for particular applications.

In a first aspect of the invention, compounds of formula I are provided:

wherein,

-   L¹, L² and L³ together with the attached carbons of the aromatic    ring form a 5-12 member ring containing 0-4 heteroatoms of N, O, S,    P and/or Si;-   L¹, L², and L³ are each independently selected from a group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   U and V are each independently CH, N, CF, CCl, or CCN;-   W, X, and Z are each independently C or N;-   Y is NR^(N), N, O, S, Se, or —CR^(a)R^(b);-   R^(N) is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₄₋₅ heterocycle,    aryl, heteroaryl, amide, sulfonamide, or carbamate;-   R^(a), R^(b) are each independently hydrogen, methyl, or together    form a C₃₋₆ cycloalkyl bearing 0-1 heteroatom of O or NR³;-   R¹ is selected from the group consisting of hydrogen, halide, —CF₃,    —CN, —C(O)H, —C(O)OR⁶—, —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe,    —C(═NOMe)NHR⁷, C(═NOH)NHR⁷, —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰,    —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S.

In a first embodiment of the first aspect,

is selected from the group consisting of

wherein,

-   L¹, L² and L³ together with the attached carbons of the aromatic    ring form a 5-12 member ring containing 0-4 heteroatoms of N, O, S,    P and/or Si;-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together form a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S.

In a second embodiment of the first aspect,

is selected from the group consisting of

wherein,

-   L¹, L² and L³ together with the attached carbons of the aromatic    ring form a 5-9 member ring containing 0-4 heteroatoms of N, O, S, P    and/or Si;-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—NR³—,    —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl,    alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl,    amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NR⁷)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together form a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S.

In a third embodiment of the first aspect, R¹ is hydrogen, halide,—C(O)OR⁶—, —C(O)NHR⁷, —C(═NR⁷)OMe, —C(O)N(OH)R⁷, —C(═NOMe)NHR⁷,C(═NOH)NHR⁷, —CH(CF₃)NHR⁸, —CH(CN)NHR⁹,

wherein,

-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl; and-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy.

In a fourth embodiment of the first aspect, R¹ is hydrogen, Br, I,—COOH, —C(O)OMe, —C(O)OEt, —C(O)OtBu, —C(O)NHMe, —C(O)NHOMe,—C(═NOMe)NHMe, —C(═NOH)NHMe, —C(═NMe)OMe, —C(O)N(OH)Me, —C(O)NHS(O)₂Me,—CH(CF₃)NHMe, —CH(CN)NHMe, —C(═NCN)NHMe,

In a fifth embodiment of the first aspect, R¹ is —C(O)NHMe or

In a sixth embodiment of the first aspect, R² is selected from the groupconsisting of

wherein each phenyl moiety is optionally substituted with 0-2 nitrogenatoms;

-   R¹² is selected from the group of hydrogen, halide, —CN, —OCHF₂,    —OCF₃, alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl, aryloxy,    alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl, sulfonamide,    carbamate;-   m is 0, 1, 2, 3, or 4;-   G is O, NR^(N), S, or CR^(a)R^(b);-   A is N, O, S, or CR^(a)R^(b); and-   D, E are each independently C or N.

In a seventh embodiment of the first aspect, R² is selected from thegroup consisting of

wherein each phenyl moiety is optionally substituted with 0-2 nitrogenatoms;

-   R¹² is selected from the group consisting of hydrogen, halide, —CN,    —OCHF₂, —OCF₃, alkyl, cycloalkyl, alkoxy, cycloalkoxy, arylalkyl,    aryloxy, alkenyl, alkynyl, amide, alkylsulfonyl, arylsulfonyl,    sulfonamide, carbamate;-   m is 0, 1, 2, 3, or 4;-   G is O, NR^(N), S, or CR^(a)R^(b);-   A is N, O, S, or CR^(a)R^(b); and-   D, E are each independently C or N.

In an eighth embodiment of the first aspect, R² is selected from thegroup consisting

wherein each phenyl moiety is optionally substituted with 0-2 nitrogenatoms.

In a ninth embodiment of the first aspect, R² is

In a tenth embodiment of the first aspect,

is selected from the group consisting

wherein,

-   L¹, L², and L³ are each independently selected from the group    consisting of a bond, —O—, —C(R¹⁵R¹⁶), —NR³—, —S(O)_(n)—,    —P(O)_(n)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted alkyl,    alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NMe)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyls,    cyclopropyl, C₁₋₄ alkoxys, or cyclopropoxy;-   R¹² is C₁₋₃ alkyl, cyclopropyl —OMe, or —NHMe;-   R¹³ is hydrogen, —Ac, or —S(O)₂Me;-   R¹⁴ is hydrogen or Me;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together form a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    form a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   A¹ and A² are each independently —CR^(a)R^(b)—, —N(R^(N))—, or —O—.

In an eleventh embodiment of the first aspect,

is selected from the group consisting of

wherein,

-   L¹, L², and L³ are each independently selected from the group of    divalent substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NMe)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R⁶ is hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl, or benzyl;-   R⁷ is hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy,    alkylsulfonyl, or cycloalkylsulfonyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, C₁₋₄ alkyl,    cyclopropyl, C₁₋₄ alkoxy, or cyclopropoxy;-   R¹² is C₁₋₃ alkyl, cyclopropyl —OMe, or —NHMe;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together form a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   A² is independently —CR^(a)R^(b)—, —N(R^(N))—, or —O—.

In a twelfth embodiment of the first aspect,

wherein,

-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R¹ is selected from hydrogen, halide, —CF₃, —CN, —C(O)H, —C(O)OR⁶—,    —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NMe)OMe, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,    —CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

-   R² is a substituted or unsubstituted aryl or heteroaryl;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl; and-   R¹⁵ and R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkyene, C₂₋₄ alkyne, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄ alkenyl.

In a second aspect of the invention is a compound having the structure:

wherein

is selected from the group consisting of

R¹ is selected from the group consisting of

and R² is selected from the group consisting of

In yet another embodiment, R¹ is

and R² is

One group of exemplary high-activity compounds are identified by ID NOS:B5, B15, B20, B33, B35, B45, B67, B85, B92, B94, B107, B118, B120, B121,B127, B128, B130, B131, B132, B138, B139, B145, B148, B158, B163, B168,B169, B171, B187, B190, B191, B192, B196, B197, B198, B201, B207, B208,B212, B214, B218, B221, B226, B232, B233, B236, B237, B238, B239, andB240 in Appendix A, and a second group of high-activity compounds areidentified by ID NOS: B2, B3, B4, B6, B7, B9, B16, B18, B19, B22, B29,B31, B32, B34, B36, B47, B48, B54, B55, B57, B60, B63, B71, B84, B93,B100, B101, B106, B108, B109, B111, B112, B113, B115, B116, B119, B123,B124, B134, B136, B137, B142, B144, B146, B147, B150, B151, B153, B154,B155, B156, B157, B159, B160, B161, B162, B164, B165, B166, B167, B170,B172, B173, B174, B175, B176, B178, B179, B180, B181, B183, B184, B186,B188, B189, B193, B195, B199, B200, B202, B203, B204, B205, B210, B215,B216, B217, B219, B220, B222, B223, B224, B225, B227, B228, B229, B230,B231, B234, B235, and B241.

As can be appreciated, the compounds in this embodiment may besubdivided into subsets wherein

is:

(i) a 7 or 8 member aliphatic ring, as exemplified by compounds B5, B15,B35, B67, B85, B92, B120, B130, B198, B94, and B130;

(ii) a 7 or 8 member ring having an internal oxygen atom, as exemplifiedby compounds B45, B118, B148, B197, B168, B187, B190; B192, B196, B207,B214, B191, B212, B218, B221, B222, B226, B232, B233, B236, B237, B238,B239, and B240;

(iii) a 7 or 8 member ring having a second internal nitrogen atom, asexemplified by compounds B107, B139, B145, B171, and B208; and

(iv) a fused 7 or 8 member ring, as exemplified by compounds B127, B128,B131, B132, B138, B158, B163, B169, B189, and B201.

In a third aspect of the invention is a compound of formula II

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted alkyl,    alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents,-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a fourth aspect of the invention is a compound that has thestructure:

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ or L² is independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl;-   R¹⁵ and R¹⁶ are independently hydrogen, hydroxyl, azide, C₂₋₄    alkyenes, C₂₋₄ alkynes, C₁₋₄ alkyls, cyclopropyl, C₁₋₄ alkoxys, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenyls; and-   R¹⁷ is H, F, Cl, or CN.

In a fifth aspect of the invention is a compound of formula IV

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are independently methyl, ethyl, or cyclopropyl; and-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

In a sixth aspect of the invention is a compound of formula V

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group consisting    of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—, —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—,    —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy, cycloalkyl,    cycloalkoxy, heterocycle, aryl, heteroaryl, amide, carbamate, urea,    and sulfonamide;-   n is 0, 1, or 2;-   R^(N) is hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₄₋₅ heterocycle,    aryl, heteroaryl, amide, sulfonamide, or carbamate;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a seventh aspect of the invention is a compound of formula VI

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In an eighth aspect of the invention is a compound of formula VII

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

In a ninth aspect of the invention is a compound of formula VIII

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ or L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—, —P(O)—,    —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted alkyl, alkenyl, alkoxy,    cycloalkyl, cycloalkoxy, heterocycle, aryl, heteroaryl, amide,    carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents,-   R³ is selected from the group of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a tenth aspect of the invention is a compound of formula X

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl; and-   R¹⁵, R¹⁶ is each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are a 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

In an eleventh aspect of the invention is a compound of formula XI

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S;-   R¹⁷ is H, F, Cl or CN; and-   V is CH, N, CF, CCl, or CCN.

In a twelfth aspect of the invention is a compound of formula XII

wherein,

-   L¹, L² and —N(SO₂Me)- together with the attached carbons of the    aromatic ring form a 5-12 member ring containing 1-4 heteroatoms of    N, O, S, P and/or Si;-   L¹ and L² are each independently selected from the group of divalent    substituents consisting of a bond, —O—, —C(R¹⁵R¹⁶)—, —NR³—,    —S(O)_(n)—, —P(O)—, —Si(R⁴R⁵)—, —C(O)—, —C(O)O—, and substituted    alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycle, aryl,    heteroaryl, amide, carbamate, urea, and sulfonamide;-   n is 0, 1, or 2;-   R² is an aryl or heteroaryl and may be substituted with one or more    R¹⁷ substituents;-   R³ is selected from the group consisting of hydrogen, alkylcarbonyl,    cycloalkylcarbonyl, alkoxylcarbonyl, cycloalkoxycarbonyl,    alkylsulfonyl and cycloalkylsulfonyl;-   R⁴ and R⁵ are each independently methyl, ethyl, or cyclopropyl;-   R¹⁵, R¹⁶ are each independently hydrogen, hydroxyl, azide, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkyl, cyclopropyl, C₁₋₄ alkoxy, or    cyclopropoxy or R¹⁵ and R¹⁶ together are a carbonyl or C₁₋₄    alkenylidene or R¹⁵ and R¹⁶ joined together with the attached carbon    are 3-6 member ring optionally containing 0-3 heteroatoms of O,    NR^(N) and/or S; and-   R¹⁷ is H, F, Cl or CN.

A thirteenth aspect of the invention provides a pharmaceuticalcomposition comprising the compounds of the invention.

A fourteenth aspect of the invention provides use of the compounds ofthe invention in the manufacture of a medicament.

In a first embodiment of the fourteenth aspect, the medicament is forthe treatment of hepatitis C.

A fifteenth aspect of the invention provides a method of treatinghepatitis C comprising administering to a subject in need thereof, atherapeutically effective amount of a compound of the invention.

General Synthesis

The compounds of the invention may be prepared by a variety of syntheticroutes, samples of them are illustrated in the synthetic schemesoutlined below. In general, the synthesis starts with constructing thecentral scaffolds such as benzofuran, benzothiophene, imidazopyridine orpyrazolopyridine by employing various synthetic techniques known tothose skilled in the art. (e.g. in Heterocyclic Chemistry, J. A. Jouleand K. Mills, J Wiley and Sons, 2010.). Once the properly substitutedcores are made, further functional group manipulations including but notlimited to chain elongation, amidation, esterification, and cyclizationare performed as necessary to lead to the target molecules. When beingallowed chemically and in some cases necessary, the central cores may bepreferred to be introduced toward the end of the synthesis. Often,protection-deprotection and, in some cases, orthogonalprotection-deprotection strategies are required to accomplish thedesired transformation. More comprehensive descriptions of thesesynthetic methodologies, techniques, etc., can be in found in these andother references: Comprehensive Organic Transformations, R. C. LarockEd., Wiley-RCH, 1999; Protective Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) ed. J Willey and Sons, 1999.

The following abbreviations are used throughout this application:

-   ACN Acetonitrile-   AcOH Acetic acid-   aq Aqueous-   Boc tert-Butoxycarbonyl-   Bu Butyl-   Cbz Benzoxylcarbonoyl-   Coned. Concentrated-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCC N,N-dicyclohexylcarbodiimide-   DCM Dichloromethane-   DEAD Diethyl azodicarboxylate-   DIEA (DIPEA) Diisopropylethylamine-   DMA N,N-Dimethylacetamide-   DMB 2,4-Dimethoxybenzyl-   DMAP N,N-dimethyl-4-aminopyridine-   DME 1,2-Dimethoxyethane-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   DPPA Diphenylphosphoryl azide-   dppp 1,3-Bis(diphenylphosphino)propane-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   DCI 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride-   EC₅₀ Effective concentration to produce 50% of the maximal effect-   ESI Electrospray Ionization-   Et₃N, TEA Triethylamine-   EtOAc, EtAc Ethyl acetate-   EtOH Ethanol-   g Gram(s)-   h or hr Hour(s)-   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   Hex Hexanes-   HOBt 1-Hydroxybenzotriazole-   HPLC High performance liquid chromatography-   IC₅₀ The concentration of an inhibitor that causes a 50% reduction    in a measured activity-   LC-MS Liquid Chromatography-Mass Spectrometry-   μM Micromolar(s)-   MeI Methyl Iodide-   MeOH Methanol-   min Minute(s)-   mM Millimolar(s)-   mmol Millimole(s)-   MαNP 2-Methoxy-2-(1-naphthyl)propionic acid-   Ms Mesyl, Methylsulfonyl-   MSH O-(mesitylsulfonyl)hydroxyamine-   mw Microwave-   NBS N-Bromosuccinimide-   NIS N-Iodosuccinimide-   nM Nanomolar-   NMO N-methylmorpholine-N-oxide-   NMP N-methylpyrrolidinone-   NMR Nuclear magnetic resonance-   PE Petroleum ether-   PG Protective Group-   PPA Polyphosphoric Acid-   PPh₃ Triphenylphosphine-   Py, Pyr Pyridine-   rt Room temperature-   SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride-   TBAF Tetra-n-butylammonium fluoride-   TEA Triethylamine-   TfOH Trifluoromethanesulfonic acid-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin Layer Chromatography-   TMSOTf Trimethylsilyl trifluoromethanesulfonate-   t_(R) Retention time-   Ts Tosyl, Methylphenylsulfonyl-   w/w Weight/weight-   v/v Volume/volume

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H NMR spectra wererecorded on a Bruker 400 MHz or 500 MHz NMR spectrometer. Significantpeaks are tabulated in the order: multiplicity (s, singlet; d, doublet;t, triplet; q, quartet; m, multiplet; br s, broad singlet), couplingconstant(s) in Hertz (Hz) and number of protons. Electrospray sprayionization (ESI) mass spectrometry analysis was conducted on aHewlett-Packard 1100 MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Mass spectrometry results are reported asthe ratio of mass over charge, followed by the relative abundance ofeach ion (in parentheses) or a single m/z value for the M+H (or, asnoted, M−H) ion containing the most common atomic isotopes. Isotopepatterns correspond to the expected formula in all cases. Normally theanalyte was dissolved in methanol at 0.1 mg/mL and 5 microliters wasinfused with the delivery solvent into the mass spectrometer, whichscanned from 100 to 1500 daltons. All compounds could be analyzed in thepositive ESI mode, using an acetonitrile/water gradient (10%-90%)acetonitrile in water with 0.1% formic acid as delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery solvent.Enantiomeric purity was determined using a Hewlett-Packard Series 1050system equipped with a chiral HLPC column (ChiralPak AD, 4.6 mm×150 mm)and isocratic elution using 5:95 isopropanol-hexane as mobile phase.

The compounds were named using the ChemDraw program from Cambridge SoftInc.

Scheme A describes a general approach to building fused rings withdifferent sizes that are attached to benzazole moieties and somechemical transformations on these fused rings. Reduction of NO₂substituted benzazole A-1, followed by sulfonylation gives A-3, in whichis installed a substituted terminal alkyne to afford A-5. A[Pd]-mediated ring cyclization (Heck reaction) forms A-6. Alternatively,A-6 can be prepared using A-7 as a starting material for the Heckreaction. Hydrogenation of A-6 generates A-8, which can also be obtainedfrom A-10 by hydrogenation. A-10 can be converted from A-6 through anisomerization. Cleavage of the double bond of A-6 using conditions suchas onzonolysis gives A-9, which can be readily converted into A-11 toA-21 following typical reduction, α-alkylation, O-alkylation,elimination, and/or hydrogenation conditions.

Scheme B describes a general approach to B-3 bearing two substituents atthe benzylic carbon. N-alkylation of A-3 with B-1 gives B-2, which isreadily converted to B-3 through an intra-molecular Heck reaction whenX¹ is a halide. When X¹ is —OR(R═H, Me, iPr etc), B-3 can be preparedusing B-4 as a precursor.

Scheme C describes a general approach to cyclopropyl-substituted analogsC-1, C-2, C-3 and C-4 from A-6, A-10, A-13 and A-18, respectively.

Scheme D describes a general approach to analog D-2 from A-6.Hydroboration of A-6 gives D-1, in which the —OH can be readilyconverted into its mesylate, tosylate, or halide. Subsequentnucleophilic substitution with a nucleophile generates D-2.

Scheme E describes an alternative approach to build fused rings withdifferent sizes that are attached to benzazole moieties. A Sonogashirareaction of either A-1 or E-3 and E-1 gives E-2, which is hydrogenatedto afford E-4. Selective sulfonylation of E-4, followed by ring closureforms A-14. Conversion the triple bond of E-2 into a carbonyl group,followed by reduction of the —NO₂, sulfonylation and ring closuregenerates A-9.

Scheme F describes a general approach to analogs F-4 and F-7 from A-2.Sulfonylation of F-1 with F-2 gives F-3, which undergoes cyclization toafford F-4. Similarly, F-7 can be prepared using F-6 instead of F-2 toreact with F-1.

Scheme G describes a general approach to fused analogs G-6, G-7, G-8,G-12 and G-14. Carrying out a Heck reaction of A-1 with G-1 gives G-2,which can also be prepared from E-2. Reduction of G-2, followed bysulfonylation affords G-3, which is the key precursor to the followingtransformations that give various fused analogs G-6, G-7, G-8, G-12 andG-14.

Scheme H describes a general way to prepare H-5, H-6 and H-7. Suzukicoupling of A-1 and H-1 gives H-2, which is converted to H-4 followingthe same strategy depicted in Scheme E. Further transformations of H-4may readily afford H-5, H-6 and H-7. Similarly, H-9 can be synthesizedby replacing A-1 with suitable starting materials.

Scheme I describes general ways to build a functionalized benzofuranmoiety. O-protection of I-1, followed by the Sonogashira reaction with asubstituted alkyne gives I-3, which is de-protected in the presence ofan acid to afford I-4. This compound undergoes a [Pd]-mediated ringcyclization to form I-5, which can be readily converted to I-7 byfollowing a two-step sequence of saponification and amide formation.Alternatively, I-4 can be converted to I-5 through a two-steptransformation of NIS or NBS-promoted cyclization and [Pd] mediatedcarbonylation.

Scheme J describes a general way to build a functionalizedpyrazole-pyridine moiety. N-amination of J-1 gives pyridium salt J-2,which undergoes a ring cyclization with alkynecarboxylate J-3 to formsubstituted pyrazole-pyridine J-4. Saponification of J-4, followed byamide formation affords J-5.

Scheme K describes a general way to build a functionalizedimidazole-pyridine moiety. Cyclization of substituted aminopyridine K-1with bromo-ketoester K-2 gives the cyclized product K-3, which can bereadily converted to K-4 by following a two-step sequence ofsaponification and amide coupling.

Scheme L describes a general way to build a functionalizedbenzothiophene moiety. Sonogashira reaction of L-1 with a substitutedalkyne gives L-2, which is converted to thio-ether L-3. An I₂-promotedring cyclization of L-3 affords benzothiophene L-4. The iodo group canbe readily transformed into a carboxylate to form functionalized L-5,which undergoes saponification and amide formation to give L-6.

Scheme M describes general ways to build a functionalized 2H-indazolemoiety. A Cu-mediated N-arylation gives a mixture of 1H-inzaole M-2 andthe desired 2H-indazole M-3. The latter can be readily converted to M-4following a two-step sequence of saponification and amide formation.Alternatively, 2H-indazole M-5 can be brominated at the C-3 position togive M-6, which undergoes a [Pd]-mediated carbonylation to afford M-3.

Scheme N describes a general way to build a functionalized indolemoiety. A condensation of N-1 and keto-ester N-2 gives N-3. Reduction ofN-3, followed by a ring formation affords substituted indole N-4, whichcan be readily converted to N-5 by following a two-step sequence ofsaponification and amide formation.

TABLE 1 Substituted benzofuran analogs

R¹

R²

R¹⁴ —H —F —Cl —Me —CF₃ V CH N C—Me C—F C—Cl

TABLE 2 Substituted pyrazole-pyridine analogs

R¹

R²

R¹⁴ —H —F —Cl —Me —CF₃ V CH N C—Me C—F C—Cl

TABLE 3 Substituted imidazole-pyridine analogs

R¹

R²

R¹⁴ —H —F —Cl —Me —CF₃ V CH N C—Me C—F C—Cl

TABLE 4 Substituted indole analogs

R¹

R²

R¹⁴ —H —F —Cl —Me —CF₃ V CH N C—Me C—F C—Cl

TABLE 5 Substituted benzothiophene analogs

R¹

R²

R¹⁴ H —F —Cl —Me —CF₃ V CH N C—Me C—F C—Cl

TABLE 6 Substituted indazole analogs

R¹

R²

R¹⁴ —H —F —Cl —Me —CF₃ V CH N C—Me C—F C—Cl

The following examples illustrate the preparation and antiviralevaluation of compounds within the scope of the invention. Theseexamples and preparations which follow are provided to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Step 1. Refer to Scheme 1. To a solution of compound 1-1 (40.0 g, 325mmol) in water (40 mL) were sequentially added compound 1-2 (12 g, 162mmol), Cu(OAc)₂ (0.6 g, 3.25 mmol) and CuI (0.6 g, 3.25 mmol). Afterstirring at 100° C. for 48 hrs, the reaction mixture was cooled to rtand added 30% (w/w) aq. NaOH (20 mL). The resulting mixture wasextracted with EtOAc (60 mL×3) and aq. phase was adjusted to pH 7 to 8by adding coned. aq. HCl. The resulting mixture was concentrated toremove water in vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH=60/1 to 10/1 (v/v)) to give compound 1-3 (18 g,57% yield) as a brown solid. LC-MS (ESI): m/z 196 [M+H]⁺.

Step 2. A mixture of compound 1-3 (40.0 g, 20.5 mmol) in polyphosphoricacid (PPA) (100 mL) was mechanically stirred at 90° C. for 3 hrs. Themixture was cooled to 60° C. and ice water (50 mL) was added withstirring for 30 min. Subsequently, the mixture was extracted with EtOAc(120 mL×3). The organic extracts were combined, washed with water (40mL) and brine (40 mL), and dried over anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(DCM/MeOH=100/1 (v/v)) to give compound 1-4 (18 g, 50% yield) as ayellow solid. LC-MS (ESI): m/z 178 [M+H]⁺.

Step 3. A solution of compound 1-4 (4.00 g, 22.6 mmol) and Et₃N (9.40mL, 67.8 mmol) in DCM (200 mL) was added MsCl (6.46 g, 56.4 mmol) at 0°C. After stirring at rt for 3 hrs, the reaction was quenched by addingice water (250 mL) and the aq. phase was extracted with DCM (100 mL×2).The organic extracts were combined, washed with water and brine, anddried over anhydrous Na₂SO₄. The solvent was removed that the residuewas purified by silica gel column chromatography (DCM/MeOH=400/1 (v/v))to give compound 1-5 (4.5 g, 78% yield) as a yellow solid. LC-MS (ESI):m/z 256 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J=9 Hz, 1H), 7.27(d, J=3.5 Hz, 1H), 6.79 (dd, J₁=9 Hz, J₂=2 Hz, 1H), 4.19 (t, J=6.5 Hz,2H), 3.89 (s, 3H), 3.06 (s, 3H), 2.79 (t, J=6.5 Hz, 2H) ppm.

Step 4.To a suspension of Ph₃PCH₃Br (14.0 g, 39.2 mmol) in 130 mL of THFwas added n-BuLi (2.5 M in hexane, 15.7 mL, 39.2 mmol) at 0° C. Afterstirring at 0° C. for 2 hr, a solution of compound 1-5 (4.00 g, 15.7mmol) in anhydrous THF (30 mL) was added. After stirring at rtovernight, the reaction mixture was quenched by adding aq. NH₄Cl (sat.,20 mL). The mixture was extracted with EtOAc (600 mL×2) and the combinedorganic extracts were washed with water (100 mL) and brine (100 mL), anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (DCM) to give compound 1-6(1.2 g, 30% yield). LC-MS (ESI): m/z 254 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃): δ 7.75 (d, J=9 Hz, 1H), 7.12 (d, J=2.5 Hz, 1H), 6.78 (dd, J₁=9Hz, J₂=3 Hz, 1H), 5.59 (s, 1H), 4.91 (s, 1H), 3.76 (s, 3H), 3.73 (t, J=6Hz, 2H), 3.08 (s, 3H), 2.70 (t, J=6 Hz, 2H) ppm.

Step 5. To a solution of compound 1-6 (2.70 g, 10.7 mmol) in dry toluene(200 mL) was added ZnEt₂ (1 M in hexane, 85.4 mL, 85.4 mmol), followedby CH₂I₂ (46 g, 171 mmol) at 0° C. After stirring at rt overnight, thereaction mixture was partitioned between EtOAc (100 mL) and 5% HCl (100mL). The organic layer was dried with anhydrous Na₂SO₄ and concentratedand the residue was purified by silica gel column chromatography (DCM)to give compound 1-7 (2.1 g, 72% yield). LC-MS (ESI): m/z 268 [M+H]⁺; ¹HNMR (500 MHz, CDCl₃): δ 7.33 (d, J=2.5 Hz, 1H), 6.66 (dd, J₁=14 Hz, J₂=3Hz, 1H), 6.61 (d, J=9 Hz, 1H), 3.95-3.92 (m, 2H), 3.78 (s, 3H), 2.91 (s,3H), 1.81-1.83 (m, 2H), 1.01 (dd, J₁=6.5 Hz, J₂=5 Hz, 2H), 0.85 (dd,J₁=6.5 Hz, J₂=Hz, 2H) ppm.

Step 6. To a solution of compound 1-7 (290 mg, 1.09 mmol) in DCM (10 mL)was added NBS (194 mg, 1.09 mmol) at 0° C. After stirring at rt for 1hr, the reaction mixture was concentrated and the residue was purifiedby silica gel column chromatography (Petroleum ether/ethyl acetate=10/1(v/v)) to give compound 1-8 (220 mg, 59% yield) as a yellow oil. LC-MS(ESI): m/z 346 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.39 (s, 1H), 6.84 (s,1H), 3.93 (t, J=5.5 Hz, 2H), 3.88 (s, 3H), 2.90 (s, 3H), 1.81 (t, J=5.5Hz, 2H), 1.03 (t, J=5 Hz, 2H), 0.89 (t, J=5 Hz, 2H) ppm.

Step 7. To a solution of compound 1-8 (200 mg, 0.58 mmol) in CH₂Cl₂ (6mL) was added BBr₃ (4 N in DCM, 0.6 mL, 2.4 mmol) at −20° C. Afterstirring at 0° C. for 1 hr, the reaction was quenched by addingice-water (50 mL). The mixture was extracted with DCM (50 mL×2) and thecombined extracts were washed with water and brine, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/ethyl acetate=10/1(v/v)) to give compound 1-9 (120 mg, 63% yield) as a red solid. LC-MS(ESI): m/z 331 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.44 (s, 1H), 6.77 (s,1H), 5.47 (br s, 1H), 3.89-3.92 (m, 2H), 2.95 (s, 3H), 2.90 (s, 3H),1.81 (t, J=5.5 Hz, 2H), 0.89-1.01 (m, 2H), 0.87-0.89 (m, 2H) ppm.

Step 8. To a solution of compound 1-9 (1.60 g, 4.82 mmol) in 30 mL THFwas added DMAP (30 mg) and TEA (1.46 g, 14.46 mmol). The resultingmixture was cooled to 0° C. and SEMCl (1.60 g, 9.64 mmol) was added.After stirring at rt for 10 hrs, the reaction mixture was poured intowater (50 mL) and extracted with EtOAc (60 mL×3). The combined organicextracts were washed brine (30 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give crudecompound 1-10 (2.2 g, 99% yield) as a yellow oil. LC-MS (ESI): m/z 485[M+Na]⁺.

Step 9. To a solution of compound 1-10 (1.60 g, 3.47 mmol) in 20 mL ofDMF were added 1-11 (0.50 g, 4.16 mmol), CuI (33 mg, 0.17 mmol),Pd(PPh₃)₂Cl₂ (244 mg, 0.35 mmol), P(t-Bu)₃ (140 mg, 0.69 mmol) andpiperidine (1.18 g, 13.9 mmol). The resulting mixture was flushed withAr and stirred at 80° C. overnight. Subsequently, the reaction mixturewas cooled to rt, poured into water (60 mL), and extracted with EtOAc(100 mL×2). The combined organic extracts were washed with water (50mL×3) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/acetone=10/1 (v/v)) to give compound 1-12 (780 mg, 45% yield) as ayellow oil. LC-MS (ESI): m/z 524 [M+Na]⁺.

Step 10. To a solution of compound 1-12 (750 mg, 1.50 mmol) in dioxane(10 mL) was added 4 N HCl/dioxane (2 mL). After stirring at rt for 2hrs, the reaction mixture was concentrated and the residue was dried invacuo to give crude compound 1-13 (600 mg, quantitative yield) as ayellow oil. LC-MS (ESI): m/z 372 [M+H]⁺.

Step 11. To a solution of compound 1-13 (600 mg, 1.62 mmol) in MeOH (20mL) was added NaOAc (265 mg, 3.24 mmol), K₂CO₃ (448 mg, 3.24 mmol),PdCl₂ (28 mg, 0.16 mmol), and CuCl₂ (653 mg, 4.86 mmol). The resultingmixture was flushed with CO and stirred at rt overnight under anatmosphere of CO. The mixture was diluted with EtOAc (80 mL) andfiltered through Celite®545. The filtrate was washed with water (30 mL)and brine (30 mL), and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/acetone=16/1 (v/v)) to give compound 1-14 (70 mg, 10%yield) as a white solid. LC-MS (ESI): m/z 429 [M+H]⁺.

Step 12. To a solution of compound 1-14 (70 mg, 0.16 mmol) in MeOH/THE(1 mL/2 mL) was added LiOH (0.65 mmol). After stirring at 70° C. for 2hr, the reaction mixture was cooled to rt and acidified by adding 1N aq.HCl (7 mL). The resulting mixture was filtered and the solid was driedin vacuo to give compound 1-15 (60 mg, 91% yield) as a white solid.LC-MS (ESI): m/z 454 [M+K]⁺.

Step 13. To a solution of compound 1-15 (60 mg, 0.14 mmol) in DMF (1.5mL) was added HATU (66 mg, 0.17 mmol). After stirring at rt for 30 min,the mixture were added DIPEA (181 mg, 1.40 mmol) and MeNH₂.HCl (47 mg,0.70 mmol). The resulting mixture was stirred at rt for 20 min andpoured into water (50 mL). The suspension was filtered and the obtainedsolid was purified by silica gel column chromatography (DCM/MeOH=600/1(v/v)) to give compound 1-16 (30 mg, 50% yield) as a white solid. LC-MS(ESI): m/z 429 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.93 (s, 1H), 7.85(dd, J₁=8.5 Hz, J₂=5.5 Hz, 2H), 7.26 (d, J=3 Hz, 1H), 7.19 (t, J=8.5 Hz,2H), 5.74 (br s, 1H), 3.99 (t, J=6.0 Hz, 2H), 2.98 (d, J=5.0 Hz, 3H),2.89 (s, 3H), 1.88 (t, J=6.0 Hz, 2H), 1.17-1.19 (m, 2H), 0.90-0.93 (m,2H) ppm.

Step 1. Refer to Scheme 2. A suspension of NaH (16.1 g, 402 mmol) inanhydrous DMF (300 mL) was cooled to 0° C. with stirring under argon,compound 2-1 (20.0 g, 134 mmol) in anhydrous DMF (200 mL) was added andthe mixture was stirred at 0° C. under argon for 1 hr. The mixture wasthen allowed to warm to rt and MeI (22.8 g, 161 mmol) was added. Afterstirring at rt for 1 hr, the reaction was quenched by adding ice water(3000 mL). The resulting mixture was extracted with EtOAc (500 mL×3) andthe combined organic extracts were washed with water and brine and driedwith anhydrous MgSO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 2-2 (12.5 g, 65% yield) as a brown oil.LC-MS (ESI): m/z 160 [M+H]⁺.

Step 2. A solution of compound 2-2 (12.5 g, 79 mmol) and PtO₂ (1.1 g,4.8 mmol) in MeOH (500 mL) was stirred at rt for 16 hrs under anatmosphere of H₂. The reaction mixture was filtered through Celite® 545and the filtrate was concentrated. The residue was purified by silicagel column chromatography (EtOAc/petroleum ether=1/8 (v/v)) to givecompound 2-3 (9.0 g, 78% yield) as a yellow oil. LC-MS (ESI): m/z 164[M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 6.84 (d, J=8.5 Hz, 1H), 6.20 (dd,J₁=8.5 Hz, J₂=2.5 Hz, 1H), 6.04 (d, J=2.5 Hz, 1H), 3.73 (s, 3H),3.26-3.28 (m, 2H), 2.69 (t, J=6.5 Hz, 2H), 1.91 (dd, J_(j)=6.5 Hz,J₂=4.5 Hz, 2H) ppm.

Step 3. To a solution of compound 2-3 (9.0 g, 55 mmol) and TEA (13.6 g,135 mmol) in DCM (200 mL) at 0° C. was added MsCl (9.1 g, 80 mmol).After stirring at rt for 30 min, the reaction mixture was added icewater (250 mL). The mixture was extracted with DCM (100 mL×2) and thecombined organic extracts were washed with water and brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (EtOAc/Petroleum ether=1/6(v/v)) to give compound 2-4 (10.6 g, 80% yield) as a yellow oil. LC-MS(ESI): m/z 242 [M+H]⁺.

Step 4. N-iodosuccinimide (NIS) (19.8 g, 88.0 mmol) was added to asolution of compound 2-4 (10.6 g, 44 mmol) in CHCl₃ (200 mL) at 0° C.After stirring at rt for 16 hrs, the reaction mixture was concentratedand the residue was purified by silica gel column chromatography(EtOAc/Petroleum ether=1/6 (v/v)) to give compound 2-6 (12.6 g, 80%yield). LC-MS (ESI): m/z 368 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.52 (s,1H), 7.32 (s, 1H), 3.86 (s, 3H), 3.81-3.79 (m, 2H), 2.88 (s, 3H), 2.77(t, J=6.5 Hz, 2H), 1.95 (t, J=5.5 Hz, 2H) ppm.

Step 5. A solution of BBr₃ (13.6 mL/4.0M, 54.4 mmol) in DCM was added toa solution of compound 2-5 (5.04 g, 13.6 mmol) in CH₂Cl₂ (100 mL) at−20° C. After stirring at −20° C. for 1 hr, the reaction mixture wasadded ice water (200 mL). The resulting mixture was extracted with DCM(100 mL×2) and the combined organic extracts were washed water and brineand dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by silica gel column chromatography (EtOAc/Petroleumether=1/12 (v/v)) to give compound 2-6 (1.4 g, 25% yield) as a whitesolid. LC-MS (ESI): m/z 354 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.42 (s,2H), 5.31 (s, 1H), 3.78 (t, J=6 Hz, 2H), 2.93 (s, 3H), 2.76 (t, J=6.5Hz, 2H), 1.95 (t, J=5.5 Hz, 2H) ppm.

Step 6. To a solution of compound 2-6 (1.2 g, 3.4 mmol) in 20 mL THF wasadded DMAP (20 mg), followed by Et₃N (0.69 g, 6.8 mmol) at rt. Theresulting mixture was cooled to 0° C. and SEMCl (0.68 g, 4.08 mmol) wasadded. After stirring at rt for 3 hrs, the reaction mixture was pouredinto ice water (50 mL). The resulting mixture was extracted with EtOAc(60 mL×3) and the combined organic extracts were washed with brine (30mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give crude compound 2-7 (1.6 g,quantitative yield) as a yellow oil. LC-MS (ESI): m/z 506 [M+Na]⁺.

Step 7. To a solution of 2-7 (1.60 g, 3.31 mmol) in 20 mL DMF were added2-8 (0.48 g, 4.0 mmol), CuI (32 mg, 0.17 mmol), Pd(PPh₃)₂Cl₂ (232 mg,0.330 mmol), P(t-Bu)₃ (133 mg, 0.660 mmol) and piperidine (1.13 g, 13.2mmol). The resulting mixture was flushed with Ar and stirred at 80° C.overnight. The resulting mixture was poured in to ice water (60 mL) andextracted with EtOAc (100 mL×2). The combined organic extracts werewashed with water (250 mL×5) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Acetone/petroleum ether=1/10 (v/v)) to give compound 2-9(1.2 g, 76% yield) as a yellow oil. LC-MS (ESI): m/z 498 [M+Na]⁺.

Step 8. To a solution of compound 2-9 (1.2 g, 2.52 mmol) in 16 mLdioxane was added 4 N HCl in dioxane (7.6 mL) at rt. After stirring atrt for 30 min, the reaction mixture was concentrated and the residue wasdried in vacuo to give crude compound 2-10 (870 mg, quantitative yield)as a yellow oil, which was used directly for the next step withoutpurification. LC-MS (ESI): m/z 346 [M+H]⁺.

Step 9. To a solution of compound 2-10 (600 mg, 1.74 mmol) in MeOH (17mL) were added NaOAc (285 mg, 3.48 mmol), K₂CO₃ (481 mg, 3.48 mmol),PdCl₂ (31.0 mg, 0.17 mmol) and CuCl₂ (702 mg, 5.22 mmol) and theresulting mixture was flushed with CO. After stirring at rt overnight,the mixture was concentrated and the residue was diluted with EtOAc (100mL) and filtered. The filtrate was washed with water (30 mL) and brine(30 mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography(Acetone/petroleum ether=1/10 (v/v)) to give compound 2-11 (140 mg, 20%yield) as a yellow solid. LC-MS (ESI): m/z 404 [M+H]⁺.

Step 10. To a solution of compound 2-11 (140 mg, 0.35 mmol) in MeOH/THF(2 mL/4 mL) was added LiOH.H₂O (58 mg, 1.4 mmol) at rt. After stirringat 70° C. for 1 hr, the reaction mixture was cooled to 0° C. andacidified with 1N aqueous HCl (3 mL). The suspension was filtered andthe solid was dried in vacuo to give compound 2-12 (136 mg, quantitativeyield) as a white solid, which was used directly for the next stepwithout further purification. LC-MS (ESI): m/z 390 [M+H]⁺.

Step 11. To a solution of compound 2-12 (60 mg, 0.15 mmol) in DMF (2 mL)was added HATU (68.4 mg, 0.18 mmol). The resulting mixture was stirredat rt for 30 min and then N,N-diisopropylethylamine (DIFA or DIPEA) (194mg, 1.5 mmol) and MeNH₂.HCl (52 mg, 0.77 mmol) were added. Afterstirring at rt for 20 min, the reaction mixture was poured into icewater (50 mL). The suspension was filtered and the collected solid waspurified by silica gel column chromatography to give compound 2-13 (20mg, 33% yield). LC-MS (ESI): m/z 403 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.88-7.93 (m, 3H), 7.60 (s, 1H), 7.19 (t, J=9.0 Hz, 2H), 5.80 (br s,1H), 3.85-3.89 (m, 2H), 3.00 (d, J=4.5 Hz, 3H), 2.95 (t, J=6.5 Hz, 2H),2.89 (s, 3H), 2.01-2.06 (m, 2H) ppm.

Step 1. Refer to Scheme 3. A mixture of compound 3-1 (2.00 g, 5.16 mmol)(prepared by following the procedures described in WO200759421 with somemodifications) and 10% Pd/C (1.0 g) in EtOAc (40 mL) was stirred at rtfor 2 hr under an atmosphere of H₂. The reaction mixture was filteredand the filtrate was concentrated to give compound 3-2 (1.7 g, 92%yield). LC-MS (ESI): m/z 358 [M+H]⁺.

Step 2. To a solution of compound 2 (1.70 g, 4.76 mmol) and TEA (1.32mL, 9.52 mmol) in DCM (50 mL) was added MsCl (0.660 g, 5.71 mmol) at 0°C. After stirring at rt for 30 min, the reaction mixture was added icewater (250 mL). The mixture was extracted with DCM (100 mL×2) and thecombined organic extracts were washed with water and brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=5/1(v/v)) to give compound 3-3 (2.07 g, quantitative yield) as a yellowsolid. LC-MS (ESI): m/z 436 [M+H]⁺.

Step 3. To a solution of compound 3-3 (4.00 g, 9.5 mmol) in DMF (50 mL)was added K₂CO₃ (5.25 g, 38.0 mmol) and compound 3-4 (1.54 g, 11.4 mmol)at rt. After stirring at 80° C. overnight, the reaction mixture waspoured into ice water (60 mL). The resulting mixture was extracted withEtOAc (100 mL×2) and the combined organic extracts were washed withwater and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give crude compound 3-5 (4.2 g, 92% yield)as a yellow solid. LC-MS (ESI): m/z 512 [M+Na]⁺.

Step 4. To a solution of compound 3-5 (2.1 g, 4.3 mmol) in CH₂Cl₂ (100mL) was added BCl₃ (1 N in DCM, 12.9 mL) at −78° C., the solution wasallowed to stirred at −30° C. for 1 hr and then quenched with ice-water(200 mL). The mixture was extracted with DCM (100 mL×2) and the combinedorganic extracts were washed with water and brine, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 3-6 (1.7 g, 86% yield) as a yellow solid.LC-MS (ESI): m/z 448 [M+H]⁺.

Step 5. To a solution of compound 3-6 (3.30 g, 7.37 mmol) in CH₂Cl₂ (160mL) were sequentially added DMAP (45 mg, 0.37 mmol), DIEA (2.58 mL, 14.8mmol) and Tf₂O (1.5 mL, 8.9 mmol) at 0° C. After stirring at 0° C. for20 min, the reaction mixture was added ice-water (100 mL). The organiclayer was washed with water and brine and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=5/1 (v/v)) to give compound3-7 (3.2 g, 86% yield) as a yellow solid. LC-MS (ESI): m/z 602 [M+Na]⁺.

Step 6. To a solution of compound 3-7 (3.00 g, 5.18 mmol) in 20 mL DMFwas added Pd(OAc)₂ (116 mg, 0.520 mmol), PPh₃ (136 mg, 0.520 mmol), LiCl(242 mg, 5.70 mmol) and Et₃N (1.44 mL, 10.4 mmol) at rt. The resultingmixture was flushed with Ar and stirred at 120° C. overnight. Themixture was cooled to rt and poured into 60 mL water. The resultingmixture was extracted with EtOAc (100 mL×2) and the combined organicextracts were washed with water (50 mL×3) and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/EtOAc=6/1 (v/v)) to give amixture of compounds 3-8 and 3-8′ (1.4 g, 63% yield) as a yellow solid.LC-MS (ESI): m/z 430 [M+H]⁺.

Step 7. To a solution of compounds 3-8 and 3-8′ (1.00 g, 2.33 mmol) inMeOH/THF (14 mL/14 mL) was added LiOH (335 mg, 13.97 mmol). Theresulting mixture was stirred at 80° C. for 1 hr, cooled to rt andacidified with 1N aq. HCl (5 mL). The suspension was filtered and thesolid was washed with water and dried in vacuo to give a mixture ofcompounds 3-9 and 3-9′ (980 mg, 98% yield) as a white solid, which wasused directly for the next step. LC-MS (ESI): m/z 402 [M+H]⁺.

Step 8. To a solution of compounds 3-9 and 3-9′ (950 mg, 2.37 mmol) inDMF (5 mL) was added HATU (1.35 g, 3.55 mmol). The resulting mixture wasstirred at rt for 30 min and added DIEA (3.30 mL, 19.0 mmol) andMeNH₂.HCl (639 mg, 9.47 mmol). After stirring at rt for 20 min, thereaction mixture was poured into ice water (50 mL). The suspension wasfiltered and the solid was purified by silica gel column chromatographyto give a mixture of compounds 3-10 and 3-10′ (580 mg, 59% yield). LC-MS(ESI): m/z 415 [M+H]⁺. Compound 3-10 was readily converted to compound3-10′ in CH₂Cl₂ in the presence of TFA. LC-MS (ESI): m/z 415 [M+H]⁺; ¹HNMR (500 MHz, CDCl₃): δ 7.93-7.96 (m, 2H), 7.74 (s, 1H), 7.71 (s, 1H),7.26-7.29 (m, 2H), 5.96 (s, 1H), 4.38 (br s, 1H), 2.98 (s, 3H), 2.74 (s,3H), 2.23 (s, 3H) ppm.

Step 9. A mixture of compounds 3-10 and 3-10′ (41.4 mg, 0.10 mmol) andPd(OH)₂ (22 mg) in EtOAc (20 mL) and MeOH (2 mL) was stirred at rt for 3hr under an atmosphere of H₂. The reaction mixture was filtered throughCelite® 545 and the filtrate was concentrated. The residue was purifiedby re-crystallization (hexane/EtOAc=10/1 (v/v)) to give compound 3-11(23 mg, 55% yield) as a while solid. LC-MS (ESI): m/z 417 [M+H]⁺; ¹H NMR(500 MHz, CDCl₃): δ 7.92 (s, 1H), 7.86-7.89 (dd, J₁=8.5 Hz, J₂=5.5 Hz,2H), 7.70 (s, 1H), 7.26 (s, 2H), 7.17-7.20 (t, J=8.5 Hz, 2H), 5.93 (brs, 1H), 3.89-3.92 (m, 1H), 3.84-3.86 (m, 1H), 3.03-3.06 (m, 1H), 3.00(d, 3H), 2.89 (s, 3H), 2.13-2.16 (m, 1H), 1.70-1.73 (m, 1H), 1.42 (d,3H) ppm.

Step 1. Refer to Scheme 4. To a solution of compound 3-1 (4.00 g, 10.3mmol) in CH₂Cl₂ (30 mL) was added BCl₃ (1 N in CH₂Cl₂, 20.6 mmol) at 0°C. After stirring at rt for 1 hr, the reaction mixture was added icewater (100 mL). The mixture was extracted with CH₂Cl₂ (800 mL×2) and thecombined organic extracts were washed with water and brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 4-1 (3.4 g, 96% yield) as a yellowsolid. LC-MS (ESI): m/z 346 [M+H]⁺.

Step 2. To a solution of compound 4-1 (3.4 g, 9.8 mmol) in CH₂Cl₂ (100mL) were added DMAP (120 mg, 0.980 mmol) and DIEA (1.52 g, 11.8 mmol),followed Tf₂O (3.20 g, 11.3 mmol) at 0° C. After stirring at 0° C. for 2hrs, the reaction mixture was added ice water (100 mL). The organiclayer was separated, washed with water and brine, and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 4-2 (4.6 g, quantitative yield) as a yellowsolid. LC-MS (ESI): m/z 478 [M+H]⁺.

Step 3. To a solution of 4-2 (2.0 g, 4.2 mmol) in 20 mL DMF was added4-3 (0.44 g, 6.3 mmol), CuI (0.16 g, 0.84 mmol), Pd(PPh₃)₂Cl₂ (0.29 g,0.42 mmol) and Et₃N (20 mL). The resulting mixture was flushed with Ar,stirred at rt for 1 hr and poured into ice water (100 mL). The mixturewas extracted with EtOAc (50 mL×5) and the combined organic extractswere washed with water and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/acetone=4/1 (v/v) to 3/2 (v/v)) to give compound 4-4(1.10 g, 69% yield) as a gray solid. LC-MS (ESI): m/z 398 [M+H]⁺.

Step 4. To a solution of compound 4-4 (2.00 g, 5.03 mmol) in EtOAc (150mL) was added 10% Pd/C (2.0 g). The resulting mixture was flushed withH₂ and stirred at rt for 1.5 hrs. Subsequently, the reaction mixture wasfiltered through Celite®545 and the filtrate was concentrated and driedin vacuo to give compound 4-5 (1.8 g, 97% yield). LC-MS (ESI): m/z 372[M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.98-8.01 (m, 2H), 7.70 (s, 1H),7.12-7.16 (m, 2H), 6.82 (s, 1H), 4.39 (dd, J₁=14.5 Hz, J₂=7 Hz, 2H),3.73 (t, J=6 Hz, 3H), 2.66 (t, J=7.5 Hz, 2H), 1.69-1.80 (m, 4H), 1.40(t, J=7 Hz, 3H) ppm.

Step 5. To a solution of compound 4-5 (1.80 g, 4.85 mmol) in CH₂Cl₂ (50mL) was added DMAP (6 mg) and anhydrous pyridine (3.07 g, 38.8 mmol),followed by MSCl (1.60 g, 14.5 mmol) at 0° C. After stirring at rt for 2hrs, the reaction mixture was added ice water (50 mL). The organic layerwas separated, washed with water and brine and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/acetone=5/1 (v/v)) to givecompound 4-6 (1.4 g, 55% yield) as a yellow solid. LC-MS (ESI): m/z 449[M-Ms+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.02-8.05 (m, 2H), 7.90 (s, 1H),7.71 (s, 1H), 7.16-7.19 (m, 2H), 6.61 (s, 1H), 4.42 (dd, J₁=14 Hz,J₂=7.0 Hz, 2H), 4.34 (t, J=5.5 Hz, 2H), 3.04-3.08 (m, 6H), 2.83 (t,J=8.0 Hz, 2H), 1.81-1.92 (m, 4H), 1.41 (t, J=7.0 Hz, 3H) ppm.

Step 6. To a suspension of NaH (0.21 g, 60% in mineral oil, 5.31 mmol)in anhydrous THF (160 mL) was added a solution of compound 4-6 (1.40 g,2.65 mmol) in anhydrous THF (40 mL) at 0° C. After stirring at rt for 2hrs, the reaction mixture was added sat. aq. NH₄Cl (10 mL). Theresulting mixture was concentrated and the residue was diluted withEtOAc (100 mL). The mixture was washed with water and brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/acetone=5/1 (v/v)) to give compound 4-7 (1.1 g, 96% yield) as ayellow solid. LC-MS (ESI): m/z 432 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ8.02-8.06 (m, 2H), 7.90 (s, 1H), 7.60 (s, 1H), 7.15-7.20 (m, 2H), 4.42(dd, J₁=14 Hz, J₂=6.5 Hz, 2H), 3.69 (t, J=6.0 Hz, 2H), 3.07 (s, 3H),3.02 (t, J=6.0 Hz, 2H), 1.94 (dd, J₁=11 Hz, J₂=5.5 Hz, 2H), 1.77 (br s,2H), 1.40-1.43 (m, 3H) ppm.

Step 7. To a solution of compound 4-7 (50 mg, 0.12 mmol) in MeOH/THF (2mL/4 mL) was added LiOH (2.0 N, 0.46 mmol). The resulting mixture wasstirred at 70° C. for 2 hrs, cooled to rt and acidified with 1 N aq. HCl(5 mL). Subsequently, the suspension was filtered and the solid waswashed with waster and dried in vacuo to give crude compound 4-8 (46 mg,95% yield) as a white solid, which was used directly for the next stepwithout further purification. LC-MS (ESI): m/z 404 [M+H]⁺.

Step 8. To a solution of compound 4-8 (46 mg, 0.12 mmol) in DMF (2 mL)was added HATU (54 mg, 0.14 mmol). The resulting mixture was stirred atrt for 30 min and added DIEA (154 mg, 1.20 mmol) and MeNH₂.HCl (41 mg,0.60 mmol). After stirring at it for 20 min, the reaction mixture waspoured into ice water (50 mL). The suspension was filtered and the solidwas purified by silica gel column chromatography (Petroleumether/acetone=3/1 (v/v)) to give compound 4-9 (30 mg, 61% yield) as awhite solid. LC-MS (ESI): m/z 417 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.89-7.92 (m, 2H), 7.68 (s, 1H), 7.59 (s, 1H), 7.19 (t, J=9.0 Hz, 2H),5.80 (d, J=4.0 Hz, 1H), 3.69 (d, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.98-3.03(m, 5H), 1.93 (dd, J₁=11 Hz, J₂=5.5 Hz, 2H), 1.75 (d, J=2.5 Hz, 2H) ppm.

Synthesis of Compound 4-9′. Following Scheme 4 by replacing compound 4-3(but-3-yn-1-01) with pen-4-yn-1-ol, compound 4-9′ was obtained as a paleyellow solid. LC-MS (ESI): m/z 431 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.92 (m, 2H), 7.71 (s, 1H), 7.43 (s, 1H), 7.19 (t, J=8.5 Hz, 2H), 5.86(s, 1H), 3.08 (m, 5H), 3.01 (d, J=4.5 Hz, 3H), 1.59 (m, 6H) ppm.

Synthesis of Compound 4-9″. Following Scheme 4 by replacing compound 4-3(but-3-yn-1-ol) with hex-5-yn-1-ol, compound 4-9″ was obtained as ayellow solid. LC-MS (ESI): m/z 447 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.93 (m, 2H), 7.68 (s, 1H), 7.35 (s, 1H), 7.18 (t, J=8.5 Hz, 2H), 5.86(s, 1H), 4.05 (m, 1H), 3.47 (m, 1H), 3.37 (m, 1H), 3.00-3.02 (m, 6H),2.76 (m, 1H), 1.90-1.95 (m, 2H), 1.73-1.79 (m, 1H), 1.26-1.65 (m, 4H),1.06 (m, 1H) ppm.

Synthesis of Compound 4-10. A mixture of compound 4-8 (50 mg, 0.12 mmol)in SOCl₂ (1.5 mL) was stirred at 80° C. for 2 hrs. The solvent wasremoved and the residue dried in vacuo to give the crude acid chloride,which was used for the next step without further purification.Subsequently, the crude acid chloride was dissolved in anhydrouspyridine (1.5 mL), followed by O-methylhydroxylamine hydrochloride (124mg, 0.490 mmol). After stirring at 100° C. for 1.5 hrs, the reactionmixture was concentrated and the residue was purified by preparativeHPLC to give compound 4-10 (20 mg, 37% yield) as a white powder. LC-MS(ESI): m/z 433 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.31 (s, 1H),7.90-7.93 (m, 2H), 7.66 (s, 1H), 7.20 (t, J=8.5 Hz, 2H), 3.85 (s, 3H),3.03 (s, 3H), 2.97-3.00 (m, 2H), 1.93-1.96 (m, 2H), 1.69-1.76 (m, 2H)ppm.

Step 1. Refer to Scheme 5. To a suspension of Zn (3.92 g, 60.3 mmol) inEtOH (80 mL) was added HOAc (3 mL), followed by solution of compound 5-1(2.0 g, 8.6 mmol) in EtOH (20 mL) at rt. After stirring at rt overnight,the reaction mixture was filtered. The filtrate was concentrated and theresidue was diluted with EtOAc (150 mL). The mixture was washed withwater (200 mL) and brine (100 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=19/1 (v/v)) to give compound 5-2(1.15 g, 48% yield) as a yellow oil. LC-MS (ESI): m/z 202 [M+H]⁺.

Step 2. A solution of compound 5-2 (10.0 g, 49.8 mmol) in anhydrouspyridine (50 mL) was added MsCl (4.04 mL, 52.2 mmol) at 0° C. Afterstirring at rt for 30 min, the reaction mixture was diluted with EtOAc(200 mL). The mixture was washed with 1 N aq. HCl (100 mL×3) and brine(100 mL) and dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was purified by silica gel column chromatography (Petroleumether/EtOAc=10/1 (v/v)) to give compound 5-3 (9.3 g, 67% yield) as awhite solid. LC-MS (ESI): m/z 280 [M+H]⁺.

Step 3. To a solution of compound 5-3 (800 mg, 2.86 mmol) in DMF (10 mL)were added compound 5-4 (511 mg, 3.43 mmol) and K₂CO₃ (1.58 g, 11.4mmol). After stirring at 80° C. for 4 hrs, the reaction mixture wasadded ice-water (50 mL) and EtOAc (50 mL). The organic layer was washedwith water (50 mL×5) and brine (50 mL) and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (Petroleum ether/Acetone=10/1 (v/v)) to givecompound 5-5 (980 mg, 99% yield). LC-MS (ESI): m/z 347 [M+H]⁺.

Step 4. To a solution of compound 5-5 (980 mg, 2.83 mmol) in DMF (5 mL)were added Pd(OAc)₂ (64 mg, 0.28 mmol), PPh₃ (297 mg, 1.13 mmol), LiCl(132 mg, 3.11 mmol) and Et₃N (572 mg, 5.66 mmol) and the resultingmixture was flushed with Ar and stirred at 120° C. for 1.5 hrs.Subsequently, the reaction mixture was cooled to rt and poured intowater (60 mL). The mixture was extracted with EtOAc (100 mL×2) and thecombined organic extracts were washed with water (50 mL×5) and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/Acetone=10/1 (v/v)) to give compound 5-6 (600 mg, 79% yield) as ayellow oil. LC-MS (ESI): m/z 268 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.20(d, J=8.5 Hz, 1H), 7.04 (d, J=2 Hz, 1H), 6.84 (dd, J₁=8.5 Hz, J₂=2.5 Hz,1H), 5.17 (s, 1H), 5.06 (s, 1H), 3.80-3.83 (m, 5H), 2.85 (s, 3H), 2.45(t, J=6 Hz, 2H), 1.89-1.93 (m, 2H) ppm.

Step 5. To a solution of compound 5-6 (3.60 g, 13.5 mmol) in toluene (60mL) were added ZnEt₂ (1 M in hexane, 108 mmol) and CH₂I₂ (57.6 g, 216mmol) at 0° C. After stirring at rt overnight, the reaction mixture wasdiluted with EtOAc (100 mL) and the resulting mixture was washed with 5%(w/w) aq. HCl (100 mL) and brine and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=20/1 to 8/1 (v/v)) to givecompound 5-7 (2.5 g, 66% yield) as a yellow solid. LC-MS (ESI): m/z 282[M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.18 (d, J=8.5 Hz, 1H), 6.92 (d, J=1.5Hz, 1H), 6.75 (dd, J₁=8.5 Hz, J₂=2 Hz, 1H), 3.78 (s, 3H), 3.61 (br s,2H), 3.06 (s, 3H), 1.92 (br s, 2H), 1.52 (br s, 2H), 0.90 (br s, 2H),0.73 (br s, 2H) ppm.

Step 6. To a solution of compound 5-7 (1.80 g, 6.43 mmol) in DCM (65 mL)was added NBS (2.28 g, 12.9 mmol) at 0° C. After stirring at rt for 24hrs, the reaction mixture was concentrated and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=15/1 (v/v))to give compound 5-8 (860 mg, 38% yield) as a white solid. LC-MS (ESI):m/z 360 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.44 (s, 1H), 6.98 (s, 1H),3.88 (s, 3H), 3.65 (br s, 2H), 3.09 (s, 3H), 1.90 (br s, 2H), 1.52 (brs, 2H), 0.90 (br s, 2H), 0.75 (br s, 2H) ppm.

Step 7. To a solution of compound 5-8 (800 mg, 2.23 mmol) in CH₂Cl₂ (30mL) was added BBr₃ (4 N in DCM, 8.91 mmol) at 0° C. After stirring at 0°C. for 20 min, the reaction mixture was poured into ice-water (150 mL).The resulting mixture was extracted with DCM (50 mL×2) and the combinedorganic extracts were washed with water and brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 5-9 (670 mg, 87% yield) as a white solid.LC-MS (ESI): m/z 346 [M+H]⁺.

Step 8. To a solution of compound 5-9 (670 mg, 1.94 mmol) in THF (30 mL)were added DMAP (20 mg) and TEA (588 mg, 5.82 mmol). The resultingmixture was cooled to 0° C. and SEMCl (643 mg, 3.87 mmol) was added.After stirring at rt for 1.5 hrs, the reaction mixture was poured intowater (50 mL). The mixture was extracted with EtOAc (60 mL×3) and thecombined organic extracts were washed with brine (30 mL) and driedanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=10/1 (v/v))to give compound 5-10 (460 mg, 50% yield) as a white solid. LC-MS (ESI):m/z 498 [M+Na]⁺.

Step 9. To a solution of compound 5-10 (460 mg, 0.970 mmol) in DMF (6mL) were added compound 1-11 (139 mg, 1.16 mmol), CuI (9.3 mg, 0.050mmol), Pd(PPh₃)₂Cl₂ (68 mg, 0.097 mmol), P(t-Bu)₃ (39 mg, 0.19 mmol) andpiperidine (330 mg, 3.88 mmol). The resulting mixture was flushed withAr and stirred at 80° C. overnight. Subsequently, the reaction mixturewas added into water (60 mL) and extracted with EtOAc (50 mL×2). Thecombined organic extracts were washed with water (50 mL×5) and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue purifiedby column chromatography (Petroleum ether/EtOAc=10/1 to 6/1 (v/v)) togive compound 5-11 (300 mg, 60% yield) as a yellow oil. LC-MS (ESI): m/z538 [M+Na]⁺.

Step 10. To a solution of compound 5-11 (280 mg, 0.54 mmol) in THF (15mL) was added TBAF (851 mg, 3.26 mmol) under an atmosphere of Ar. Afterrefluxing overnight, the reaction mixture was concentrated and theresidue was purified by silica gel column chromatography (Petroleumether/EtOAc=8/1 (v/v)) to give compound 5-12 (100 mg, 48% yield) as ayellow solid. LC-MS (ESI): m/z 86 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.78-7.83 (m, 2H), 7.51 (s, 1H), 7.48 (s, 1H), 7.11-7.16 (m, 2H), 6.89(s, 1H), 3.64-3.69 (m, 2H), 3.16 (s, 3H), 1.96 (br s, 2H), 1.59 (br s,2H), 1.01 (br s, 2H), 0.81 (br s, 2H) ppm.

Step 11. To a solution of compound 5-12 (80 mg, 0.21 mmol) in TFA (0.5mL) and CHCl₃ (0.5 mL) was added NIS (70 mg, 0.31 mmol) at rt. Afterstirring at for 3 hrs, the reaction mixture was concentrated and theresidue was purified by silica gel column chromatography (Petroleumether/EtOAc=6/1 (v/v)) to give compound 5-13 (80 mg, 75% yield) as ayellow solid. LC-MS (ESI): m/z 512 [M+H]⁺.

Step 12. To a solution of compound 5-13 (80 mg, 0.16 mmol) in DMF (3 mL)and MeOH (3 mL) were added Pd(PPh₃)₄ (91 mg, 0.080 mmol) and Et₃N (64mg, 0.64 mmol). The resulting mixture was flushed with CO and stirred at60° C. for 4 hrs under an atmosphere of CO. Subsequently, the mixturewas water (20 mL) and extracted with EtOAc (60 mL×2). The combinedorganic extracts were washed with water (60 mL×5) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=8/1 (v/v)) togive compound 5-14 (70 mg, quantitative yield) as a yellow solid. LC-MS(ESI): m/z 444 [M+H]⁺.

Step 13. To a solution of compound 5-14 (70 mg, 0.16 mmol) in MeOH/THF(1 mL/2 mL) was added LiOH (0.63 mmol). After stirring at 70° C.overnight, the reaction mixture was cooled to 0° C. and acidified with 1N aq. HCl (7 mL). The suspension was filtered and the solid was washedwith water and dried in vacuo to give crude compound 5-15 (60 mg,quantitative yield) as a white solid, which was used for the next stepwithout further purification. LC-MS (ESI): m/z 430 [M+H]⁺.

Step 14. To a solution of compound 5-15 (60 mg, 0.14 mmol) in DMF (1.5mL) was added HATU (66 mg, 0.17 mmol). The resulting mixture was stirredat rt for 30 min and then DIPEA (181 mg, 1.40 mmol) and MeNH₂.HCl (47mg, 0.70 mmol) were added. The resulting mixture was stirred at rt for20 min and poured into water (50 mL). The suspension was filtered andthe solid was purified by silica gel column chromatography (Petroleumether/Acetone=9/1 (v/v)) to give compound 5-16 (10.5 mg, 18% yield) as awhite solid. LC-MS (ESI): m/z 443 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.87 (m, 2H), 7.75 (s, 1H), 7.53 (s, 1H), 7.18 (m, 2H), 5.79 (s, 1H),3.64 (br s, 2H), 3.15 (s, 3H), 3.01 (d, J=5 Hz, 3H), 1.95 (br s, 2H),1.61 (br s, 2H), 1.02 (br s, 2H), 0.82 (s, 2H) ppm.

Step 1. Refer to Scheme 6. To a solution of compound 3-3 (4.35 g, 10.0mmol) in DMF (40 mL) was added K₂CO₃ (5.52 g, 40.0 mmol) and compound6-1 (1.79 g, 12.0 mmol). After stirring at 80° C. overnight, thereaction mixture was cooled to rt and poured into water (60 mL). Themixture was extracted with EtOAc (100 mL×2) and the combined organicextracts were washed with water and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/acetone=10/1 (v/v)) to give compound 6-2(4.53 g, 90% yield) as a yellow oil. LC-MS (ESI): m/z 526 [M+Na]⁺.

Step 2. To a solution of compound 6-2 (2.0 g, 4.0 mmol) in CH₂Cl₂ (80mL) was added BCl₃ (1 N in DCM, 8.0 mmol) at −30° C. After stirring at−30 to −20° C. for 30 min, the reaction mixture was poured intoice-water (100 mL). The mixture was extracted with DCM (80 mL×2) andcombined organic extracts were washed with water and brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/acetone=7/1 (v/v)) to give compound 6-3 (1.4 g, 76% yield) as ayellow solid. LC-MS (ESI): m/z 462 [M+H]⁺.

Step 3. To a solution of compound 6-3 (1.40 g, 3.04 mmol) in CH₂Cl₂ (40mL) were added DMAP (19 mg, 0.15 mmol) and DIEA (0.590 g, 4.56 mmol),followed by Tf₂O (1.03 g, 3.64 mmol) at 0° C. After stirring at 0° C.for 20 min, the reaction mixture was added into ice water (50 mL). Theorganic layer was washed with water and brine and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/EtOAc=20/1 (v/v)) to givecompound 6-4 (1.6 g, 89% yield) as a colorless oil. LC-MS (ESI): m/z 594[M+H]⁺.

Step 5. To a solution of compound 6-4 (1.00 g, 1.69 mmol) in 20 mL DMFwas added Pd(OAc)₂ (38 mg, 0.17 mmol), PPh₃ (177 mg, 0.680 mmol), LiCl(79.0 mg, 1.86 mmol) and Et₃N (1.00 mL, 6.75 mmol). The resultingmixture was flushed with Ar and stirred at 120° C. overnight.Subsequently, the mixture was cooled to rt and poured into 60 mL water.The resulting mixture was extracted with EtOAc (80 mL×2) and thecombined organic extracts was washed with water and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/EtOAc=15/1 (v/v)) to givecompound 6-5 (610 mg, 81% yield) as a yellow solid. LC-MS (ESI): m/z 444[M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.04-8.07 (m, 2H), 7.96 (s, 1H), 7.69(s, 1H), 7.17-7.20 (m, 2H), 5.30 (s, 1H), 5.21 (d, J=2.0 Hz, 1H), 4.42(dd, J₁=14.5 Hz, J₂=7.0 Hz, 2H), 3.85 (br s, 2H), 2.87 (s, 3H), 2.53 (t,J=5.0 Hz, 2H), 1.96 (dd, J₁=12 Hz, J₂=6.0 Hz, 2H), 1.41 (t, J=6.5 Hz,3H) ppm.

Step 6. To a solution of compound 6-5 (300 mg, 0.680 mmol) in MeOH/THF(4 mL/8 mL) was added 2.0 N aq. LiOH (2.72 mL, 1.36 mmol). Afterstirring at 75° C. for 2 hrs, the reaction mixture was coiled to rt andacidified with 2 N aq. HCl to pH 5-6. The suspension was filtered andthe solid was washed with water and dried in vacuo to give compound 6-6(260 mg, 92% yield) as a white solid, which was used directly for thenext step without further purification. LC-MS (ESI): m/z 416 [M+H]⁺.

Step 7. To a solution of Et₂Zn (1.1 M in toluene, 10 mL, 11 mmol) in1,2-dichloroethane (10 mL) was added a solution of CH₂I₂ (5.87 g, 22mmol) in 1,2-dichloroethane (10 mL) at −78° C. under an atmosphere ofN₂. After stirring at −15° C. for 30 min, the mixture was cooled to −78°C. Subsequently, a solution of compound 6-6 (200 mg, 0.481 mmol) in1,2-dichloroethane (15 mL) was added. The reaction mixture was thenstirred at room temperature for 40 hrs and added 1 M aq. HCl at 0° C.The mixture was extracted with DCM (50 mL×2) and the combined organicextracts were concentrated in vacuo. The residue was added THF (20 mL),MeOH (2.5 mL), water (2.5 mL) and LiOH (76 mg). After stirring at 70° C.for 2 hrs, the mixture was treated with 1 M aq. HCl (1.5 mL) at 0° C.The mixture was concentrated and the residue was extracted with DCM (50mL×4) and the combined organic extracts were dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel chromatography to give compound 5-15 (113 mg, 55% yield). LC-MS(ESI): m/z 430 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.04 (m, 3H), 7.57 (s,1H), 7.20 (m, 2H), 3.68 (br s, 2H), 3.17 (s, 3H), 1.97 (br s, 2H), 1.64(br s, 2H), 1.06 (br s, 2H). 0.86 (s, 2H) ppm.

Step 8. To a solution of the compound 5-15 (60 mg, 0.14 mmol) in DMF(3.00 mL) was added HATU (64.0 mg, 0.168 mmol). The resulting mixturewas stirred at rt for 30 min and 2 M CH₃NH₂ in THF (1.4 mmol) was added.After stirring at rt for 30 min, the reaction mixture was concentratedand the residue was purified by preparative HPLC to give compound 5-16(20 mg, 32% yield) as a white powder. LC-MS (ESI): m/z 443 [M+H]⁺; ¹HNMR (500 MHz, CDCl₃): δ 7.87 (m, 2H), 7.75 (s, 1H), 7.53 (s, 1H), 7.18(m, 2H), 5.79 (s, 1H), 3.64 (br s, 2H), 3.15 (s, 3H), 3.01 (d, J=5 Hz,3H), 1.95 (br s, 2H), 1.61 (br s, 2H), 1.02 (br s, 2H), 0.82 (s, 2H)ppm.

Synthesis of Compound 6-7. A solution of Et₂Zn (1.1 M in toluene, 0.22mmol) in DCM (2 mL) was drop-wisely added CH₂I₂ (117 mg, 0.440 mmol) at−78° C. under an atmosphere of N₂. After stirring at −78° C. for 30 min,to the reaction mixture was drop-wisely added a mixture of compound 6-5(4.43 mg, 0.01 mmol) and TFA (0.01 mL) in DCM (1 mL). Subsequently, thereaction mixture was stirred at 60° C. for 30 min and then cooled to rtand diluted with water (25 mL) and DCM (50 mL). The organic layer wasseparated, washed with brine (25 mL), and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was dried in vacuo to givecompound 6-7. LC-MS (ESI): m/z 458.1 [M+H]⁺.

Synthesis of Compound 7-1. Refer to Scheme 7. To a solution of compound6-6 (250 mg, 0.60 mmol) in DMF (5 mL) was added HATU (275 mg, 0.72mmol). The resulting mixture was stirred at rt for 30 min before DIEA(154 mg, 1.2 mmol) and MeNH₂.HCl (122 mg, 1.8 mmol) were added in. Afterstirring at rt for 20 min, the reaction mixture was poured into water(50 mL). The suspension was filtered and the solid was washed with waterand dried in vacuo. The solid was dissolved in DCM (2 mL) and theresulting solution was added into hexane (80 mL). The suspension wasfiltered and the solid was dried in vacuo to give compound 7-1 (230 mg,90% yield) as a white solid. LC-MS (ESI): m/z 429 [M+H]⁺; ¹H NMR (500MHz, CDCl₃): δ 7.88-7.91 (m, 2H), 7.74 (s, 1H), 7.67 (s, 1H), 7.19 (t,J=9.0 Hz, 2H), 5.82 (br s, 1H), 5.28 (s, 1H), 5.19 (d, J=1.0 Hz, 1H),3.83 (br s, 2H), 3.01 (d, J=5.5 Hz, 3H), 2.86 (s, 3H), 2.51 (t, J=5.0Hz, 2H), 1.92-1.96 (m, 2H) ppm.

Synthesis of Compound 7-2. To a solution of compound 7-1 (40 mg, 0.094mmol) in DCM (4 mL) was flushed with O₃ at −78° C. until compound 7-1disappeared (about 1 min). Subsequently, the reaction mixture wassaturated with N₂ and PPh₃ (591 mg, 0.26 mmol) was added. After stirringat rt for 3 hrs, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give compound 7-2 (20 mg, 50% yield). LC-MS (ESI): m/z431 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.88 (dd, J₁=8.5 Hz, J₂=6.0 Hz,2H), 7.71 (s, 1H), 7.54 (s, 1H), 7.19 (t, J=8.5 Hz, 2H), 5.80 (br s,1H), 4.08-4.13 (m, 1H), 3.25-3.28 (m, 2H), 3.08 (s, 3H), 3.01 (d, J=4.5Hz, 3H), 1.89-2.04 (m, 2H), 1.67 (br s, 2H), 1.47 (d, J=7.0 Hz, 3H) ppm.

Synthesis of Compound 7-3. To a solution of compound 7-1 (70 mg, 0.16mmol) in EtOAc (30 mL) was added 10% Pd/C (20 mg). The resulting mixturewas flushed with H₂ and stirred at rt for 3 hr. The reaction mixture wasfiltered; the filtrate was concentrated and the residue was purified bysilica gel column chromatography (Petroleum ether/EtOAc=5/1 (v/v)) togive compound 7-3 (40 mg, 58% yield) as a white solid. LC-MS (ESI): m/z431 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (s, 1H), 7.99 (dd, J₁=8.5Hz, J₂=6.0 Hz, 2H), 7.68 (s, 1H), 7.21 (t, J=8.5 Hz, 2H), 5.89 (br s,1H), 3.90 (t, J=6.0 Hz, 2H), 3.03-3.05 (m, 6H), 2.85 (t, J=6.0 Hz, 2H),2.04-2.08 (m, 2H) ppm. Compound 7-3 was separated into a pair ofenantiomers: enantiomer 7-3_A (t_(R)=9.420 min) and enantiomer 7-3_B(t_(R)=12.173 min) detected by UV absorption at 214 nm on a ChiralPak®IA 4.0 mm×150 mm×5 μm column (eluent: hexane/EtOH=70/30 (v/v) with 0.1%diethylamine (v/v) and flow rate: 1 mL/min).

Synthesis of Compound 7-4. To a solution of compound 7-1 (50 mg, 0.12mmol) in DCM (4 mL) was added CF₃COOH (0.02 mL). After stirring at rtovernight, the reaction mixture was concentrated. The residue wasdissolved in DCM (0.5 mL) and the resulting solution was added intohexane (20 mL). The suspension was filtered and the solid was dried invacuo to give compound 7-4 (30 mg, 58% yield). LC-MS (ESI): m/z 429[M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.89 (dd, J₁=8 Hz, J₂=5.5 Hz, 2H),7.82 (s, 1H), 7.67 (s, 1H), 7.22 (t, J=8.5 Hz, 2H), 6.06 (t, J=6.5 Hz,1H), 5.80 (br s, 1H), 3.75-4.50 (m, 2H), 3.01 (d, J=4.5 Hz, 3H), 2.78(s, 3H), 2.22 (s, 3H), 2.18 (t, J=6 Hz, 2H) ppm.

Synthesis of Compound 7-5. To a solution of compound 7-2 (40 mg, 0.093mmol) in MeOH (1 mL) and THF (1 mL) was added NaBH₄ (10 mg, 0.28 mmol).After stirring at 0° C. for 10 min, the reaction was quenched by addingseveral drops of acetone. The solvent was removed and the residue wasdissolved in EtOAc (25 mL). The mixture was washed with water and driedwith anhydrous Na₂SO₄. The solvent was removed; the residue wasdissolved in DCM (0.5 mL) and the resulting solution was added intohexane (20 mL). The suspension was filtered and the solid was dried invacuo to give compound 7-5 (10 mg, 25% yield) as a white solid. LC-MS(ESI): m/z 433 [M+H]⁺; NMR (500 MHz, CDCl₃): δ 7.92-7.94 (m, 3H), 7.56(s, 1H), 7.18 (t, J=8.5 Hz, 2H), 5.87 (br s, 1H), 5.15 (br s, 1H), 3.83(br s, 1H), 3.12 (s, 3H), 3.01-3.02 (m, 4H), 2.32 (br s, 1H), 2.03 (brs, 3H) ppm.

Step 1. Refer to Scheme 8. To a stirred solution of compound 4-2 (9.00g, 18.9 mmol) in DMF (100 mL) were added Et₃N (7.84 mL, 56.6 mmol),Pd(OAc)₂ (212 mg, 0.94 mmol), dppp (469 mg, 1.13 mmol) and butyl vinylether (12.1 mL, 94.4 mmol) under an atmosphere of Ar. After stirring at100° C. for 2 hrs, the reaction mixture was concentrated. The residuewas diluted with EtOAc (250 mL) and the resulting mixture was washedwith water (100 mL×3) and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=16/1 (v/v)) to give compound 8-1 (3.9 g, 48%yield) as a yellow solid. LC-MS (ESI): m/z 427 [M+H]⁺.

Step 2. A solution of compound 8-1 (3.90 g, 9.13 mmol) in THF (60 mL)was added 1 N aq. HCl (10 mL) at rt. After stirring at rt for 15 min,the reaction mixture was concentrated and the residue was diluted withDCM (100 mL). The resulting mixture was washed with brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 8-2 (3.27 g, 96% yield) as a yellow solid,which was used for the next step without further purification. LC-MS(ESI): m/z 372 [M+H]⁺.

Step 3. To a stirred solution of compound 8-2 (2.00 g, 5.38 mmol) inEtOAc (50 mL) was added SnCl₂.2H₂O (3.47 g, 16.2 mmol). After stirringat 80° C. for 1 hr, the reaction mixture was added sat. aq. NaHCO₃ (50mL) and the resulting mixture was stirred at rt for 30 min.Subsequently, the mixture was filtered through Celite®545 and thefiltered cake was washed with EtOAc (50 mL×3). The organic layer of thefiltrate was washed with brine and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give crudecompound 8-3 (1.8 g, 98% yield) as a brown solid, which was used for thenext step without further purification. LC-MS (ESI): m/z 342 [M+H]⁺.

Step 4. To a stirred solution of compound 8-3 (900 mg, 2.64 mmol) inanhydrous pyridine (15 mL) was added MsCl (0.25 mL, 3.17 mmol) at 0° C.After stirring at rt for 1 hr, the reaction mixture was diluted withEtOAc (100 mL) and the resulting mixture was washed with 2 N aq. HCl (20mL×2) and H₂O (50 mL×3) and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/DCM/EtOAc=8/4/1 (v/v)) to compound 8-4 (520 mg, 47%yield) as a yellow solid. LC-MS (ESI): m/z 442 [M+Na]⁺.

Step 5. To a solution of compound 8-4 (380 mg, 0.91 mmol) in MeOH (10mL) and THF (10 mL) was added NaBH₄ (172 mg, 4.54 mmol) in severalportions at 0° C. After stirring at 0° C. for 15 min, the reaction wasquenched by adding acetone (1 mL). The mixture was concentrated and theresidue was diluted with EtOAc (100 mL). The resulting mixture waswashed with 2 N aq. HCl (20 mL) and H₂O (50 mL×3) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 8-5 (240 mg, 63% yield), which was used forthe next step without further purification. LC-MS (ESI): m/z 444[M+Na]⁺.

Step 6. To a stirring solution of compound 8-5 (50 mg, 0.12 mmol) in THF(15 mL) was added NaH (24 mg, 0.6 mmol) at 0° C. under an atmosphere ofAr. After stirring at rt for 15 min, the mixture was added compound 8-6(106 mg, 0.24 mmol) (prepared following the procedure described inAngew. Chem. Intl. Ed. 2008, 47, 3784) at 0° C. and the resultingmixture was stirred at 0° C. for 3 hrs and rt overnight. Subsequently,saturated aq. NH₄Cl (10 mL) was added to quench the reaction and themixture was concentrated. The residue was diluted with EtOAc (50 mL) andthe mixture was washed with brine (10 mL) and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (Petroleum ether/Acetone=4/1 (v/v)) to givecompound 8-7 (30 mg, 56% yield) as a white solid. LC-MS (ESI): m/z 448[M+H]⁺.

Step 7. To a solution of compound 8-7 (40 mg, 0.09 mmol) in MeOH/THF (2mL/4 mL) was added 2.0 N aq. LiOH (0.18 mmol, 0.36 mmol). After stirringat 75° C. for 3 hrs, the reaction mixture was cooled to 0° C. andacidified with 2N aq. HCl adjust pH value to 5-6. Subsequently, thesuspension was filtered and the solid was washed with water and dried invacuo to give compound 8-8 (38 mg, 97% yield) as a white solid, whichwas used for the next step without further purification. LC-MS (ESI):m/z 442 [M+Na]⁺.

Step 8. To a solution of compound 8-8 (40 mg, 0.10 mmol) in DMF (3 mL)was added HATU (43 mg, 0.12 mmol). The resulting mixture was stirred atrt for 60 min and DIEA (0.16 mL, 0.95 mmol) and MeNH₂.HCl (20 mg, 0.29mmol) were added. After stirring at rt for 15 min, the reaction mixturewas added into water (30 mL). The suspension was filtered and the solidwas washed with water and dried in vacuo. The residue was dissolved inDCM (1.5 mL) and the solution was added into hexane (40 mL). Theresulting suspension was filtered and the solid was dried in vacuo togive compound 8-9 (23 mg, 56% yield). LC-MS (ESI): m/z 433 [M+H]⁺; ¹HNMR (500 MHz, CDCl₃): δ 7.88-7.91 (m, 3H), 7.62 (s, 1H), 7.20 (t, J=8.5Hz, 2H), 5.80 (br s, 1H), 4.96 (q, J=6.5 Hz, 1H), 4.15-4.18 (m, 1H),4.02-4.09 (m, 2H), 3.29-3.34 (m, 1H), 3.15 (s, 3H), 3.01 (d, J=5.0 Hz,3H), 1.74 (d, J=6.5 Hz, 3H) ppm. Compound 8-9 was separated into a pairof enantiomers: enantiomer 8-9_A (t_(R)=3.34 min) and enantiomer 8-9_B(t_(R)=3.89 min) detected by UV absorption at 214 nm on a DaicelCHIRALPAK AS-H column (eluent: MeOH/liquid CO₂=10/90 (v/v), flow rate:60 g/min and back pressure: 100 bar).

Step 1. Refer to Scheme 9. To a solution of compound 4-2 (2.37 g, 5.00mmol) in anhydrous THF (70 mL) were added commercially available2-ally-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.09 g, 6.50 mmol),Pd(PPh₃)₄ (0.58 g, 0.50 mmol) and CsF (3.0 g, 19.87 mmol) under anatmosphere of Ar. The resulting mixture stirred at 80° C. 3 hrs andconcentrated. The residue was diluted with water (100 mL) and extractedwith EtOAc (50 mL×3). The combined organic extracts were washed withbrine and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/EtOAc=200/1 (v/v)) to give compound 9-1 (670 mg, 36% yield) as ayellow solid. LC-MS (ESI): m/z 370 [M+H]⁺.

Step 2. A solution of compound 9-1 (670 mg, 1.82 mmol) in DCM (110 mL)was purged with O₃ until reaction solution turned to be light blue at−78° C. Subsequently, PPh₃ (1.19 g, 4.5 mmol) was added and the mixturewas stirred at rt overnight. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=20/1to 10/1 (v/v)) to give compound 9-2 (570 mg, 82% yield) as a yellowsolid. LC-MS (ESI): m/z 372 [M+H]⁺.

Step 3. To a solution of compound 9-2 (420 mg, 1.13 mmol) in MeOH (11mL) and THF (11 mL) was added NaBH₄ (172 mg, 4.53 mmol) at 0° C. Afterstirring at 0° C. for 30 min, several drops of acetone was added toquench the reaction. The mixture was concentrated and the residue wasdiluted with water (50 mL) and EtOAc (50 mL). The aq. phase wasextracted with EtOAc (50 mL×2) and the combined organic extracts werewashed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give crude compound 9-3(422 mg, quantitative yield), which was used for the next step withoutfurther purification. LC-MS (ESI): m/z 374 [M+H]⁺.

Step 4. To a solution of compound 9-3 (410 mg, 1.10 mmol) in EtOAc (150mL) was added 10% Pd/C (400 mg). The resulting mixture was flushed withH₂ and stirred at rt overnight under an atmosphere of H₂. Subsequently,the reaction mixture was filtered through Celite®545 and the filteredcake was washed with EtOAc (50 mL×2). The filtrate was concentrated andthe residue was dried in vacuo to give crude compound 9-4 (372 mg, 99%yield). LC-MS (ESI): m/z 344 [M+H]⁺.

Step 5. To a solution of compound 9-4 (372 mg, 1.08 mmol) in CH₂Cl₂ (10mL) were added DMAP (20 mg), Et₃N (654 mg, 6.48 mmol) and MsCl (500 mg,4.33 mmol) at 0° C. After stirring at 0° C. for 30 min and rt for 1.5hrs, the reaction mixture was added saturated aq. NaHCO₃ (5 mL). Themixture was diluted with DCM (50 mL) and the organic layer was washedwith brine and dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was purified by silica gel column chromatography (Petroleumether/Acetone=4/1 (v/v)) to give compound 9-5 (200 mg, 46% yield) as ayellow solid. LC-MS (ESI): m/z 404 [M+H]⁺.

Step 6. To a solution of compound 9-5 (200 mg, 0.500 mmol) in MeOH/THE(6 mL/12 mL) was added LiOH (2.0 N aq. solution, 2.0 mmol). Theresulting mixture was stirred at 70° C. for overnight and then acidifiedwith 1N aq. HCl (aq, 4 mL) at 0° C. The suspension was filtered and thesolid was washed with water and dried in vacuo to give crude compound9-6 (170 mg, 90% yield) as a white solid, which was used for the nextstep without further purification. LC-MS (ESI): m/z 376 [M+H]⁺.

Step 7. To a solution of compound 9-6 (70 mg, 0.18 mmol) in DMF (4 mL)was added HATU (85 mg, 0.22 mmol). The resulting mixture was stirred atrt for 30 min, followed by adding DIEA (0.33 mL, 1.8 mmol) and MeNH₂.HCl(76.0 mg, 1.12 mmol). After stirring at rt for 20 min, the reactionmixture was added into water (50 mL). The resulting suspension wasfiltered and the solid was washed with water and dried in vacuo.Subsequently, the residue was dissolved in DCM and the solution wasadded into hexane to precipitate the product. The resulting suspensionwas filtered and the solid was dried in vacuo to give compound 9-7 (40mg, 55% yield) as a white solid. LC-MS (ESI): m/z 389 [M+H]⁺; ¹H NMR(500 MHz, CDCl₃): δ 7.85-7.88 (m, 2H), 7.64 (s, 1H), 7.57 (s, 1H), 7.18(t, J=8.5 Hz, 2H), 5.82 (br s, 1H), 4.06 (t, J=8.0 Hz, 2H), 3.23 (t,J=8.0 Hz, 2H), 2.99 (d, J=4.5 Hz, 3H), 2.90 (s, 3H) ppm.

Step 1. Refer to Scheme 10. To a mixture of iPr₂NH (27 mL, 190.7 mmol)in THF (140 mL) was dropwisely added nBuLi (2.5M in Hexanes, 73 mL,181.6 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min,then warmed up to rt with stirring for another 20 min. Subsequently, toa mixture of compound 10-1 (10 g, 45.4 mmol) (prepared by following theprocedure described in WO2009051306) and I₂ (28.5 g, 114 mmol) in THF(70 mL) was dropwisely added LDA solution freshly prepared at −78° C.Compound 10-1 was consumed when 3.5 equiv of LDA was added and thereaction was quenched by adding sat. aq. NH₄Cl. The mixture was warmedup to rt and concentrated. The residue was diluted with water andextracted by EtOAc (100 mL×3). The organic extracts were combined,washed by brine, and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Hexanes/EtOAc=5/1 (v/v)) to give compound 10-2 (13 g, 83% yield) as ayellow solid. ¹H NMR (300 MHz, CDCl₃): δ 7.48 (d, 1H), 7.39 (dd, 1H),6.84 (dd, 1H), 4.42 (q, 2H), 3.83 (s, 3H), 1.45 (t, 3H) ppm.

Step 2. A mixture of compound 10-1 (3.34 g, 10 mmol), 10-2 (1.40 g, 10mmol) and Pd(PPh₃)₄ (0.58 g, 0.5 mmol) in 2 M aq. Na₂CO₃ (15 mL) anddioxane (75 mL) was degassed and refilled with nitrogen. The process wasrepeated 3 times. The mixture was then stirred at 90° C. in a sealedflask for 24 hrs. After being cooled down, the reaction mixture wasconcentrated. The residue was partitioned between DCM and water. Theaqueous layer was extracted with DCM several times. The combined organicextracts were dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was purified by silica gel column chromatography(EtOAc/hexanes=1/20 to 1/15 (v/v)) to give compound 10-3 (2.54 g, 88%yield). LC-MS (ESI): m/z 315 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 7.68 (m,1H), 7.57 (d, J=1.3 Hz, 1H), 7.46 (m, 1H), 7.44 (d, J=8.9 Hz, 1H),7.16-7.30 (m, 2H), 6.98 (dd, J=1.3 and 8.9 Hz, 1H), 4.32 (q, J=7.3 Hz,2H), 3.92 (s, 3H), 1.27 (t, J=7.3 Hz) ppm.

Step 3. To a solution of compound 10-3 (2.54 g, 8.7 mmol) in chloroformat was slowly added 70% HNO₃ (w/w, 4.7 mL, 105 mmol). After completingthe addition, the solution was stirred at −20° C. for 30 min and rtovernight. The reaction mixture was diluted with dichloromethane (150mL), washed with water (50 mL×5), and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (EtOAc/hexanes=1/9 to 1/6 (v/v)) to give compound 10-4(1.98 g, 68% yield). ¹H NMR (300 MHz, CDCl₃): δ 8.10 (s, 1H), 7.79 (s,1H), 7.69 (m, 1H), 7.56 (m, 1H), 7.20-7.36 (m, 2H), 4.35 (q, J=7.3 Hz,2H), 4.05 (s, 3H), 1.25 (t, J=7.3 Hz) ppm.

Step 4. To a solution of compound 10-4 (1.98 g, 5.91 mmol) indichloromethane at −45° C. was slowly added a solution of BBr₃ (0.68 mL,7.1 mmol) in dichloromethane (6 mL). The resulting mixture was stirredat the temperature for 30 min, and then in an ice-water bath for 30 min.Subsequently, the cold reaction mixture was diluted with dichloromethane(100 mL), and ice water (10 mL) was slowly added into the solution todestroy the excess amount of BBr₃. The organic layer was washed withwater and dried over anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give a crude de-methylated intermediate ofcompound 10-4, which was used for the next step without furtherpurification. LCMS (ESI): m/z 344 [M-1]⁺. Subsequently, Cs₂CO₃ (3.85 g,12 mmol) was added into a solution of the above crude product in NMP (20mL). After stirring at rt for 10 min, the reaction mixture was added2-bromopropane (0.67 mL, 7.1 mmol) and the resulting mixture was stirredat rt for 2 hrs and at 50° C. for 18 hrs. The reaction mixture was addedinto ice water (150 mL) and the mixture was extracted with EtOAc (50mL×3). The combined extracts were washed with brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 10-5 (2.15 g, 94% yield). ¹H NMR (300 MHz,CDCl₃): δ 8.04 (s, 1H), 7.78 (s, 1H), 7.68 (m, 1H), 7.57 (m, 1H),7.18-7.36 (m, 2H), 7.73 (m, 1H), 4.34 (q, J=7.3 Hz, 2H), 1.44 (d, J=7.4Hz, 6H), 1.27 (t, J=7.3 Hz, 3H) ppm.

Synthesis of Compound 11-2. Refer to Scheme 11. To a solution ofcompound 11-1 (100 mg, 0.22 mmol) in THF (6.0 mL) and water (1.5 mL),OsO₄ (1.5 mL, 4% in water, 0.23 mmol) was added at rt. The reaction wasstirred for 5 min and then NMO (0.028 mL, 0.027 mmol) was added. Afterstirring for 4 hrs, the reaction was quenched by adding Na₂SO₃ (454 mg,3.6 mmol). The reaction was extracted with dichloromethane (25 mL×2) andthe extracts were combined, washed with brine, and dried anhydrousNa₂SO₄. The solvent was removed and the residue was re-dissolved indichloromethane (5 mL). Subsequently, NaIO₄ (103 mg, 0.48 mmol), silicagel (650 mg) and water (0.2 mL) were added to the mixture at rt. Afterstirring for 4 hrs, the reaction was diluted with dichloromethane (50mL), washed with brine, and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(EtOAc/hexanes=1/10 (v/v)) to give compound 11-2 (70 mg, 70% yield).LC-MS (ESI): m/z 449 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.23 (s, 1H),7.68-7.80 (m, 1H), 7.67 (s, 1H), 6.95-7.10 (m, 2H), 5.80-5.81 (m, 1H),3.89 (t, J=6.3 Hz, 2H), 3.03 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.83-2.97(m, 2H), 2.02-2.08 (m, 2H) ppm.

Synthesis of Compound 11-3. To a solution of compound 11-1 (65 mg, 0.14mmol) in THF (6.0 mL), BH₃.SMe₂ (2M in THF, 0.22 mL, 0.44 mmol) wasadded at rt. After stirring at rt overnight, 3 N aq. NaOH (0.42 mL, 1.26mmol) was slowly added. After stirring at rt for 30 min, H₂O₂ (30% (w/w)in water, 0.42 mL) was added and the resulting mixture was stirred at rtfor another 30 min. Subsequently, the reaction mixture was diluted withEtOAc (50 mL) and the organic layer was washed with brine and water anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (EtOAc/hexanes=1/10 (v/v))to give compound 11-3 (50 mg, 77% yield). LC-MS (ESI): m/z 465 [M+H]⁺;¹H NMR (300 MHz, CDCl₃): δ 7.64-7.69 (m, 1H), 7.26 (s, 1H), 7.45 (br. s,1H), 6.85-6.98 (m, 2H), 4.04-4.15 (m, 1H), 3.55-3.80 (m, 3H), 3.83-3.89(m, 1H), 3.08 (s, 3H), 2.89 (s, 3H), 1.75-1.95 (m, 4H) ppm.

Step 1. Refer to Scheme 12. A solution of Br₂ (1 M in AcOH, 10 mL, 10mmol) was slowly added into a solution commercially available compound12-1 (1.24 g, 10 mmol) in AcOH (35 mL) at rt. After stirring at rt for 1hr, the reaction mixture was filtered and the solid was dried in vacuoto give compound 12-2 (1.41 g, 69% yield). ¹H NMR (300 MHz, CD₃OD): δ7.84 (s, 1H), 6.29 (s, 1H), 3.87 (s, 3H) ppm.

Step 2. A mixture of compound 12-2 (1.41 g, 6.9 mmol) and2-bromo-3-(4-fluorophenyl)-3-oxo-propionic acid ethyl ester (12-3) (1.01g, 3.5 mmol) in ethanol (100 mL) was stirred at 70° C. for 22 hrs. Thesolvent was removed and the residue was partitioned between DCM (50 mL)and water (25 mL). The organic layer was washed with sat. aq. Na₂CO₃solution and water and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(EtOAc/DCM=1/10 (v/v)) to give compound 12-4 (0.90 g, 65% yield). ¹H NMR(300 MHz, CDCl₃): δ 9.57 (s, 1H), 7.74-7.78 (m, 2H), 7.09-7.15 (m, 2H),7.04 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.00 (s, 3H), 1.25 (t, J=7.2 Hz,3H) ppm.

Step 3. A solution of LiOH (0.25 g, 6.0 mmol) in water (4.5 mL) wasadded into a solution of compound 12-4 (0.90 g, 2.3 mmol) in THF (9 mL).After stirring at 50° C. for 24 hrs, the reaction mixture was acidifiedto pH ˜3.0 by adding 1 N aq. HCl. The solvent was removed and theresidue was dried in vacuo to give crude compound 12-5, which was usedfor the next step without further purification. LC-MS: m/z 365 [M+H]⁺.

Step 4. A mixture of compound 12-5 (0.83 g, 2.28 mmol), CH₃NH₂.HCl (0.31g, 4.56 mmol), EDC.HCl (0.66 g, 3.42 mmol), HOBt-H₂O (0.52 g, 3.4 mmol)and DIPEA (1.88 mL, 11.4 mmol) in DMF (22 mL) was stirred at 50° C. for18 hrs. The reaction mixture was added into ice water (250 L) andfiltered. The solid was washed with water and dried in vacuo to givecrude compound 12-6. ¹H NMR (300 MHz, CDCl₃): δ 9.70 (s, 1H), 7.66-7.72(m, 2H), 7.18-7.24 (m, 2H), 6.97 (s, 1H), 5.65 (broad s, 1H, NH), 4.00(s, 3H), 2.88 (d, J=5.1 Hz, 3H) ppm.

Step 5. BBr₃ (1.73 mL, 19 mmol) was slowly added into a solution ofcompound 12-6 (0.68 g, 1.8 mmol) in DCM (4 mL) at 0° C. The resultingreaction mixture was stirred at rt for 16 hrs under an atmosphere of N₂and treated with ice water (25 mL). After adjusting the pH of themixture to basic using 5 N aq. NaOH, the mixture was extracted with DCM(25 mL×3). The combined organic extracts dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography to give compound 12-7 (0.36 g, 55% yield). LC-MS:m/z 366 [M+H]⁺.

Step 6. A mixture of compound 12-7 (0.36 g, 1.0 mmol), 5-bromo-1-pentene(163 mg, 1.1 mmol) and K₂CO₃ (113 mg, 2.0 mmol) in DMF (12 mL) wasstirred at 50° C. for 8 hrs. The reaction mixture was poured into waterand the precipitate was collected by filtration. The crude product waspurified by silica gel column chromatography (EtOAc/DCM=1/7 (v/v)) togive compound 12-8 (0.21 g, 49% yield). LC-MS: m/z 432 [M+H]⁺; ¹H NMR(300 MHz, CDCl₃): δ 9.67 (s, 1H), 7.66-7.72 (m, 2H), 7.17-7.24 (m, 2H),6.93 (s, 1H), 5.69-5.97 (m, 1H), 5.68 (br s, 1H), 5.02-5.16 (m, 2H),4.08 (t, J=6.8 Hz, 2H), 2.88 (d, J=5.2 Hz, 3H), 2.28-2.37 (m, 2H),1.96-2.06 (m, 2H) ppm.

Step 7. A mixture of compound 12-8 (200 mg, 0.46 mmol), Pd(OAc)₂ (10.3mg, 0.046 mmol), PPh₃ (48.5 mg, 0.19 mmol), LiCl (21.5 mg, 0.51 mmol)and Et₃N (0.26 mL, 1.8 mmol) in DMF (6.0 mL) was degassed and refilledwith N₂. The process was repeated for 3 times. After stirring at 120° C.for 18 hrs, the mixture was added into ice water (100 mL). Thesuspension was filtered and the solid was purified by silica gel columnchromatography (EtOAc/DCM=1/7 (v/v)) to give a mixture of compounds 12-9and 12-10 (100 mg, 62% yield) at a ratio of 3/1 determined by protonNMR. LC-MS: m/z 352 [M+H]⁺. Compound 12-9: ¹H NMR (300 MHz, CDCl₃): δ9.48 (s, 1H), 6.68-7.72 (m, 2H), 7.18-7.24 (m, 2H), 7.13 (s, 1H), 5.65(br s, 1H), 5.37 (s, 1H), 5.16 (s, 1H), 4.28-4.34 (m, 2H), 2.87 (d,J=5.2 Hz, 3H), 2.58-2.66 (m, 2H), 2.05-2.12 (m, 2H) ppm.

Synthesis of Compound 12-11. A mixture of compounds 12-9 and 12-10 (10mg, 0.028 mmol) and 10% Pd/C (5 mg) in ethanol (4 mL) was stirred at rtfor 6 hrs under an atmosphere of H₂. The mixture was filtered throughCelite®545 and the filtered cake was washed with DCM (20 mL×2). Thefiltrate was concentrated and the residue was purified by columnchromatography (EtOAc/DCM=1/7 (v/v)) to give compound 13-11 (8 mg, 80%yield). LC-MS: m/z 354 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 9.28 (s, 1H),7.72-7.78 (m, 2H), 7.63 (s, 1H), 7.16-7.28 (m, 2H), 6.06-6.14 (m, 1H),4.16-4.20 (m, 2H), 3.18-3.28 (m, 1H), 2.91 (d, J=5.2 Hz, 3H), 2.08-2.20(m, 1H), 1.90-2.05 (m, 2H), 1.68-1.78 (m, 1H), 1.42 (d, J=7.2 Hz, 3H)ppm.

Synthesis of Compound 12-10. A solution of compounds 12-9 and 12-10 (28mg) in CF₃CO₂H (3 mL) was stirred at 70° C. for 48 hrs. The solvent wasremoved and the residue was diluted with DCM (25 mL). The mixture waswith sat. aq. NaHCO₃ and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(EtOAc/DCM=1/7 (v/v)) to give compound 12-10 (22 mg, 79% yield). LC-MS(ESI): m/z 352 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 9.63 (s, 1H),7.65-7.70 (m, 2H), 7.18-7.26 (m, 3H), 6.04-6.08 (m, 1H), 5.66-5.74 (m,1H), 4.29 (t, J=5.4 Hz, 2H), 2.60 (d, J=4.8 Hz, 3H), 2.64-2.70 (m, 2H),2.26 (s, 3H) ppm.

Step 1. Refer to Scheme 13, to a solution of compound 13-1 (10.0 g, 64.9mmol) in EtOH (400 mL) was added 10% Pd/C (w/w) (4.60 g). The reactionmixture was allowed to stir at rt under an atmosphere of H₂ for 24 hrs.Subsequently, the reaction mixture was filtered through Celite® 545 andthe filtered cake was washed with EtOAc (100 mL×3). The filtrate wasconcentrated and the residue was dried in vacuo to give crude compound13-2 (8.0 g, 99% yield) as a dark red oil, which was used for the nextstep without further purification. LC-MS (ESI): m/z 125 [M+H]⁺.

Step 2. To a stirring solution of compound 13-2 (7.99 g, 64.4 mmol) andEt₃N (59.4 mL, 386 mmol) in DCM (100 mL) was dropwisely added MsCl (6.50mL, 193 mmol) at 0° C. over 30 min. After stirring at rt for 2 hrs, thereaction mixture was filtered and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (Petroleumether/acetone=6/1 to 3/2 (v/v)) to give compound 13-3 (6.9 g, 38% yield)as a yellow solid. LC-MS (ESI): m/z 281 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃):δ 8.56-8.57 (d, J=5 Hz, 1H), 8.42 (s, 1H), 6.97-6.98 (d, J=5 Hz, 1H),4.00 (s, 3H), 3.45 (s, 6H) ppm.

Step 3. To a solution of 0-(mesitylsulfonyl)hydroxyamine (MSH) (17.8mmol) in DCM (100 mL) was added compound 13-3 (5.00 g, 17.8 mmol). Afterstirring at rt overnight, the reaction mixture was concentrated and theresidue was dried in vacuo to give crude compound 13-4, which was usedfor the next step without further purification. LC-MS (ESI): m/z 297[M+H]⁺.

Step 4. To a solution of compound 13-4 (crude, 17.8 mmol) and ethyl3-(4-fluorophenyl)propiolate (3.43 g, 17.8 mmol) in DMF (80 mL) wasadded K₂CO₃ (9.82 g, 71.2 mmol) in one portion. After stirring at rt for2 hrs, the reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (Petroleumether/acetone=5/1 to 3/1 (v/v)) to give compound 13-5. LC-MS (ESI): m/z408 [M+H]⁺.

Step 5. To a solution of compound 13-5 (1.00 g, 2.45 mmol) in DMF (25mL) were added K₂CO₃ (1.02 g, 7.36 mmol) and 5-bromopent-1-ene (732 mg,4.91 mmol) at rt. After stirring at 80° C. for 2 hrs, the reactionmixture was poured into ice water (100 mL). The resulting solution wasextracted with EtOAc (100 mL×3) and the organic extracts were combined,washed with water (50 mL×3) and dried with anhydrous Na₂SO₄. The solventwas removed and the residue was purified by silica gel columnchromatography (Petroleum ether/acetone=3/1 (v/v)) to give compound 13-6(1.0 g, 86% yield) as a yellow oil. LC-MS (ESI): m/z 476 [M+H]⁺.

Step 6. A mixture of 2-(diethylamino)ethanethiol.HCl (535 mg, 3.15 mmol)and t-BuONa (637 g, 6.62 mmol) in anhydrous DMF (25 mL) was stirred atrt for 15 min under an atmosphere of N₂. Subsequently, a solution ofcompound 13-6 (1.0 g, 2.1 mmol) in anhydrous DMF (5 mL) was added andthe resulting mixture was refluxed for 30 min, poured into ice water (50mL) and kept at 0° C. The pH value of the reaction mixture was adjustedto 3 to 4 by adding 1 N aq. HCl and the resulting mixture was extractedwith EtOAc (50 mL×3). The organic extracts were combined, washed withbrine and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography(Hexanes/EtOAc=2/1 (v/v)) to give compound 13-7 (370 mg, 38% yield) as ayellow oil. LC-MS (ESI): m/z 462 [M+H]⁺.

Step 7. To a solution of compound 13-7 (164 mg, 0.35 mmol) and DMAP (2.0mg, 0.016 mmol) in CH₂Cl₂ (6 mL) was added Et₃N (100 μL, 0.72 mmol),followed by Tf₂O (70 μL, 0.42 mmol) at 0° C. After stirring at 0° C. for30 min, the reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=7/1(v/v)) to give compound 13-8 (102 mg, 48% yield) as a yellow oil. LC-MS(ESI): m/z 594 [M+H]⁺.

Step 8. A solution of compound 13-8 (215 mg, 0.36 mmol), Pd(OAc)₂ (8 mg,0.036 mmol), dppf (66 mg, 0.12 mmol) and sodium acetate (36 mg, 0.43mmol) in DMF (20 mL) was heated at 80° C. for 3 hrs under an atmosphereof N₂. The reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=5/1(v/v)) to give compound 13-9 (115 mg, 61% yield) as a white solid. LC-MS(ESI): m/z 444 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.70 (s, 1H), 8.12 (s,1H), 7.78 (m, 2H), 7.15 (m, 2H), 5.38 (s, 1H), 5.37 (s, 1H), 4.32 (q,J=7.0 Hz, 2H), 3.87 (m, 2H), 2.91 (s, 3H), 2.58 (m, 2H), 1.99 (m, 2H),1.31 (t, J=7.0 Hz, 3H) ppm.

Step 9. To a solution of compound 13-9 (95 mg, 0.21 mmol) in EtOH (40mL) and THF (10 mL) was added 10% Pd/C (40 mg). The resulting mixturewas stirred at rt for 16 hrs under an atmosphere of 1-12. The resultingmixture was filtered and the filtrate was concentrated and dried invacuo to give crude compound 13-10, which was used for the next stepwithout further purification. LC-MS (ESI): m/z 446 [M+H]⁺.

Step 10. A mixture of compound 13-10 (95 mg, 0.213 mmol) and LiOH (2.0M, 0.852 mmol) in MeOH (4 mL) and THF (8 mL) was stirred at 75° C. for48 hrs. The mixture was cooled to rt and concentrated. The residue wasdiluted with water (30 mL) and adjusted its pH value to 5˜6 by adding 2N aq. HCl. The resulting mixture was extracted EtOAc (50 mL×3) and theorganic extracts were combined, washed with brine and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 13-11 (85 mg, 95% yield) as a white solid,which was used directly for the next step without further purification.LC-MS (ESI): m/z 418 [M+H]⁺.

Step 11. To a solution of compound 13-11 (85.0 mg, 0.20 mmol) in DMF (2mL) was added HATU (93.0 mg, 0.24 mmol). After stirring at rt for 30min, the reaction mixture was added DIPEA (53 mg, 0.41 mmol) andMeNH₂.HCl (17 mg, 0.24 mmol) and the resulting mixture was stirred at rtfor 30 min. Subsequently, the reaction mixture was poured into ice waterand the suspension was filtered. The solid was collected and dried invacuo to give crude compound 13-12. LC-MS (ESI): m/z 431 [M+H]⁺; ¹H NMR(500 Hz, CDCl₃): δ 8.51 (s, 1H), 8.21 (s, 1H), 7.66 (dd, J₁=5.5 Hz,J₂=8.5 Hz, 2H), 7.23 (t, J=8.5 Hz, 2H), 5.5 (m, 1H), 4.19 (m, 1H), 3.21(m, 2H), 3.16 (s, 3H), 2.86 (d, J=4.5 Hz, 3H), 1.97-2.06 (m, 2H),1.63-1.78 (m, 2H), 1.49 (d, J=6.5 Hz, 3H) ppm. Compound 13-12 wasseparated into a pair of enantiomers: enantiomer 13-12_A (t_(R)=11.306min) and enantiomer 13-12_B (t_(R)=14.966 min) detected by UV absorptionat 214 nm on a Daicel CHIRALPAK IA 4.0 mm×150 mm×5 μm column (eluent:hexane/EtOH=70/30 (v/v) with 0.1% (v/v) diethylamine and flow rate: 1mL/min).

Step 1. Refer to Scheme 14. A mixture of compound 14-1 (10.0 g, 43.28mmol) and LiOH (5.46 g, 129.8 mmol) in THF (400 mL), MeOH (200 mL) andwater (100 mL) was stirred at 70° C. for 2 hrs under an atmosphere ofN₂. Subsequently, the reaction mixture was cooled to 0° C. and adjustedits pH value to 6 by adding coned. aq. HCl. The resulting suspension wasfiltered and the solid was dried in vacuo to give compound 14-2 (7.8 g,83% yield). LC-MS (ESI): m/z 217 [M+H]⁺.

Step 2. A mixture of compound 14-2 (7.81 g, 35.6 mmol), DPPA (9.40 mL,43.5 mmol) and Et₃N (5.90 mL, 42.5 mmol) in t-BuOH (300 mL) was stirredat 90° C. for 6 hrs under an atmosphere of N₂. The solvent was removedand the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=5/1 to 4/1 (v/v)) to give compound 14-3 (4.9 g,47% yield) as a white solid. LC-MS (ESI): m/z 234 [M-56+H]⁺.

Step 3. A mixture of compound 14-3 (5.10 g, 17.7 mmol) and methyl2-bromo-3-(4-fluorophenyl)-3-oxopropanoate (5.84 g, 21.2 mmol) in DMF(80 mL) was stirred at 80° C. for 42 hrs under an atmosphere of N₂.Subsequently, the reaction mixture was cooled to 0° C., followed byadding a solution of NaHCO₃ (1.9 g) in water (20 mL). After stirring at0° C. for 15 min, the mixture was diluted with water (100 mL) and theresulting suspension was extracted with EtOAc (100 mL×3). The organicextracts were combined, washed with water (10 mL×3) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=40/1 to 20/1(v/v)) to give compound 14-4 (1.9 g, 23% yield). LC-MS (ESI): m/z 464[M+H]⁺.

Step 4. To a solution of compound 14-4 (1.8 g, 3.9 mmol) in dioxane (10mL) was added 4N HCl in dioxane (10 mL). After stirring at rt for 3 hrs,the reaction mixture was concentrated and the residue was dried in vacuoto give crude compound 14-5, which was used for the next step withoutfurther purification. LC-MS (ESI): m/z 364 [M+H]⁺.

Step 5. To a stirred solution of compound 14-5 (1.4 g, 3.86 mmol) inpyridine (30 ml) was added MsCl (1.33 g, 11.6 mmol) at 0° C. Afterstirring at rt for 1.5 hrs, the reaction mixture was concentrated andthe residue was diluted with water (50 mL). Subsequently, the mixturewas adjusted its pH value to 5-6 by adding 2N aq. HCl. The resultingsuspension was filtered and the solid was dried in vacuo to givecompound 14-6, which was used for the next step without furtherpurification. LC-MS (ESI): m/z 520 [M+H]⁺.

Step 6. A solution of compound 14-6 (2.00 g, 3.86 mmol) and K₂CO₃ (532mg, 3.86 mmol) in MeOH (100 mL) was stirred at rt for 30 min. Thesuspension was filtered and the filtrate was concentrated. The residuewas purified by silica gel column chromatography (Petroleumether/acetone=2/1 to 1/2 (v/v)) to give compound 14-7 (970 mg, 56%yield) as a yellow solid. LC-MS (ESI): m/z 442 [M+H]⁺.

Step 7. To a solution of compound 14-7 (970 mg, 2.19 mmol) in DMF (30mL) was added K₂CO₃ (1.21 g, 8.76 mmol) and 5-bromopent-1-ene (784 mg,5.26 mmol) at rt. After stirring at 80° C. for 16 hrs and at 90° C. for24 hrs, the reaction mixture was concentrated and the residue wasdiluted with water (50 mL). The mixture was extracted with EtOAc (50mL×2). The organic extracts were combined, washed with water (50 mL×2)and dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by silica gel column chromatography (Petroleumether/acetone=5/1 (v/v)) to give compound 14-8 (380 mg, 34% yield) as ayellow solid. LC-MS (ESI): m/z 510 [M+H]⁺.

Step 8. Following the procedure described for the synthesis of compound13-11 and replacing compound 13-8 with 14-8, compound 14-12 wasobtained. LC-MS (ESI): m/z 431 [M+H]⁺; ¹H NMR (500 Hz, CDCl₃): δ 9.37(s, 1H), 7.67 (m, 2H), 7.60 (s, 1H), 7.21 (t, J=8.5 Hz, 2H), 5.72 (m,1H), 3.24 (m, 2H), 3.16 (s, 3H), 2.87 (d, J=5.0 Hz, 3H), 1.74-2.02 (m,4H), 1.48 (d, J=7.0 Hz, 3H) ppm.

Step 1. Refer to Scheme 15. To a solution of NaH (80 g, 60% mineral oildispersion, 2 mol) in toluene (1.2 L) was added diethyl carbonate (295g, 2.50 mol) at 0° C. After stirring at rt for 2 hrs, the mixture wasadded drop wise to a solution of compound 15-1 (99 g, 0.50 mol) intoluene (400 mL) at reflux. After refluxing overnight, the reactionmixture was cooled to rt and sequentially treated with HOAc (140 mL) andaq. HCl (2 M, 864 mL). The resulting mixture was extracted with EtOAc(400 mL×3) and the combined organic extracts were washed with water (500mL×4) and brine (200 mL×2) and dried with anhydrous Na₂SO₄. The solventwas removed and the residue was dried in vacuo to give compound 15-2(122 g, 90% yield) as an oil. LC-MS (ESI): m/z 271.0 [M+H]⁺.

Step 2. To a solution of compound 15-2 (100 g, 369 mmol) in DMF (70 mL)was added p-benzoquinone (40 g, 369 mmol), followed by ZnCl₂ (50 g, 369mmol) in portions at rt. After stirring at 105° C. for 3.5 hrs, thereaction mixture was partitioned between water (800 mL) and EtOAc (800mL) and filtered. The aqueous phase was extracted with EtOAc (500 mL×2).The combined organic extracts were washed with water (1000 mL×2) anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleumether/Acetone=10/1 (v/v)) to give compound 15-3 (26 g, 20% yield) as ayellow solid. LC-MS (EST): m/z 361.0 [M+H]⁺.

Step 3. To a solution of compound 15-3 (26 g, 72 mmol) in NMP (200 mL)was added Cs₂CO₃ (47.0 g, 144 mmol). After stirring at rt for 20 min,2-bromopropane (20.0 ml, 216 mmol) was added. The resulting mixture wasstirred at 80° C. for 4 hrs, then diluted with ammonia and agitated for30 min. The mixture was diluted with water (200 mL) and the aqueousphase was extracted with EtOAc (150 mL×3). The combined organic extractswere washed with water (200 mL×3) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give compound15-4 (27.5 g, 95% yield) as a colorless oil. LC-MS (ESI): m/z 403.0[M+H]⁺.

Step 4. To a solution of HNO₃ (conc. 66 mL, 0.89 mol) and CH₂Cl₂ (300mL) a solution of compound 15-4 was added drop wise (27.5 g, 68.2 mmol)in CH₂Cl₂ (120 mL) at 0° C. over 1 hr. After stirring at rt for 30 min,the reaction mixture was diluted with water (200 mL) and extracted withDCM (150 mL×3). The combined organic extracts were washed with water(200 mL×3) and dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was re-crystallized in methyl t-butyl ether (MTBE) to givecompound 15-5 (24.6 g, 80% yield) as a pale yellow solid. LC-MS (ESI):m/z 448.0 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.92 (d, J=8.5 Hz, 2H),7.87 (m, 2H), 7.76 (s, 1H), 7.65 (d, J=8.5 Hz, 2H), 4.69-4.74 (m, 1H),4.40-4.44 (m, 2H), 1.54 (s, 6H), 1.41-1.45 (t, 3H) ppm.

Step 5. A mixture of compound 15-5 (5.0 g, 11.2 mmol), 4-fluorophenol(1.7 g, 14.5 mmol), Pd(OAc)₂ (250 mg, 1.12 mmol), t-BuXphose (380 mg,0.9 mmol) and K₃PO₄ (4.8 g, 22.4 mmol) in toluene (50 mL) was stirred at100° C. under an atmosphere of Ar and monitored by LC-MS. After 2 hrs,the reaction mixture was concentrated and the residue was diluted withwater (100 mL). The mixture was extracted with EtOAc (100 mL×3) and thecombined organic extracts were washed with water (100 mL×2) and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 15-6 (4.8 g, 90% yield) as a yellowpowder. LC-MS (ESI): m/z 480.1 [M+H]⁺.

Step 6. To a solution of compound 15-6 (2.0 g, 4.2 mmol) in DCM (30 mL)drop wise was added BCl₃ (8.4 mL, 8.4 mmol) at −78° C. After stirring at−40° C. for 1 hr, the reaction was quenched by adding sat. aq. NH₄Cl (20mL). The resulting mixture was extracted with DCM (50 mL×2) and thecombined organic extracts were washed with water (50 mL×3) and brine (50mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give crude compound 15-7 (1.6 g, 90%yield) as a yellow solid. LC-MS (ESI): m/z 438.1 [M+H]⁺.

Step 7. To a solution of compound 15-7 (1.6 g, 3.9 mmol) and DMAP (24mg, 0.2 mmol) in DCM (30 mL) at 0° C. was added Et₃N (790 mg, 7.8 mmol),followed by Tf₂O (1.6 g, 5.82 mmol). After stirring at rt for 1 hr,LC-MS analysis indicated that the reaction went completion. The mixturewas diluted with DCM (100 mL), washed water (50 mL×3) and brine (50 mL)and dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas dried in vacuo to give crude compound 15-8 (1.8 g, 94% yield) as ayellow solid. LC-MS (ESI): m/z 570.0 [M+H]⁺.

Step 8. To a solution of compound 15-8 (1.8 g, 3.2 mmol) in CH₃CN (50mL) was added NaOAc (1.6 g, 16 mmol.), dppf (180 mg, 0.32 mmol), andPd(OAc)₂ (150 mg, 0.64 mmol), and the resulting mixture was saturatedwith Ar. After 1-(vinyloxy)butane (1.6 g, 16 mmol) was added, themixture was stirred at 100° C. for 2 hrs under an atmosphere of Ar.Subsequently, the reaction mixture was cooled to rt, concentrated, anddiluted with EtOAc (100 mL). The resulting mixture was washed with water(50 mL×2) and brine (100 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dissolved in THF (50 mL) and aq.HCl (2N, 12 mL). After refluxing for 1 hr, the mixture was cooled to rtand concentrated to remove most of the organic solvent. The resultingmixture was extracted with EtOAc (50 mL×2). The combined organicextracts were washed with water (50 mL×3) and brine (50 mL) and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue was driedin vacuo to give crude compound 15-9 (1.4 g, 98% yield). LC-MS (ESI):m/z 464.1 [M+H]⁺.

Step 9. To a solution of compound 15-9 (1.4 g, 3.4 mmol) in EtOAc (50mL) was added SnCl₂.H₂O (2.8 g, 13.6 mmol) at rt and the resultingmixture was stirred at 80° C. for 1 hr. The mixture was cooled to rt andd its pH value was adjusted to 8-9 by adding sat. aq. NaHCO₃. Themixture was filtered and the filtrate was extracted with EtOAc (50mL×2). The combined organic extracts were washed with water (50 mL×3)and brine (50 mL) and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give crude compound 15-10(1.1 g, 85% yield) as a yellow solid. LC-MS (ESI): m/z 434.1 [M+H]⁺.

Step 10.

To a solution of compound 15-10 (1.1 g, 2.5 mmol) in anhydrous pyridine(20 mL) was added MsCl (1.8 mL) at 0° C. After the mixture was stirredat 30° C. for 2 hrs, LC-MS analysis indicated that the reaction went tocompletion. The mixture was diluted with water (100 mL) and EtOAc (50mL). The aqueous phase was extracted with EtOAc (50 mL×3). The combinedorganic extracts were washed with sat. aq. NH₄Cl (50 mL×3) and brine (50mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give crude compound 15-11 (1.1 g, 90%yield) as a yellow solid. LC-MS (ESI): m/z 512.1 [M+H]⁺.

Step 11. To a solution of compound 15-11 (1.1 g, 2.1 mmol) in THF (30mL) was added NaBH₄ (560 mg, 14.7 mmol) in portions at 0° C. Afterstirring at 0° C. for 30 min, LC-MS analysis indicated that the reactionwent to completion and acetone (2 mL) was added to quench excess amountof NaBH₄. The mixture was concentrated and the residue was diluted withEtOAc (100 mL). The resulting mixture was washed with water (50 mL×3)and brine (50 mL) and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give compound 15-12 (0.9g, 90% yield) as a yellow solid. LC-MS (ESI): m/z 514.1 [M+H]⁺.

Step 12. To a solution of compound 15-12 (0.9 g, 1.7 mmol) in anhydrousDCM (30 mL) was added NaH (60% in paraoil, 200 mg, 5 mmol) at 0° C.,followed by compound 8-6 (1.1 g, 2.55 mmol). After stirring at 0° C. for3 hrs and at rt for 12 hrs, the reaction was quenched by adding sat. aq.NH₄Cl (10 mL). The resulting mixture was extracted with DCM (30 mL×3)and the combined organic extracts were washed with brine (50 mL) anddried with anhydrous Na₂SO₄. The solvent was removed and the residue waspurified by silica gel column chromatography (Petroleum ether/EtOAc=6/1(v/v)) to give compound 15-13 (520 mg, 55% yield) as a white solid.LC-MS (ESI): m/z 540.1 [M+H]⁺.

Step 13. To a solution of compound 15-13 (520 mg, 0.96 mmol) in MeOH/THF(4 mL/8 mL) was added aq. LiOH (2.0 M, 2 mL) at rt. After stirring at80° C. for 12 hrs, the reaction mixture was cooled to rt and adjustedits pH value to 2˜3 by adding aq. HCl (2.0 M). The organic solvent wasremoved and the residue was diluted with EtOAc (50 mL). The organiclayer was isolated, washed with brine (25 mL) and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive crude compound 15-14 (442 mg, 90% yield) as a white solid. LC-MS:(ESI): m/z 512.1 [M+H]⁺.

Step 14. Compound 15-14 (442 mg, 0.86 mmol) was dissolved in DMF (5 mL),followed by addition of HATU (450 mg, 1.17 mmol). After stirring at rtfor 1 hr, the reaction mixture was added DIPEA (503 mg, 3.9 mmol) andMeNH₂.HCl (157 mg, 2.34 mmol). The resulting mixture was stirred at rtfor another 1 hr before being concentrated. The residue was diluted withwater (25 mL) and EtOAc (50 mL). The organic layer was isolated, washedwith brine (25 mL), and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=5/1 (v/v)) to give compound 15-15 (360 mg, 80%yield) as a white solid. LC-MS (ESI): m/z 525.1 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃): δ 7.89 (s, 1H), 7.82-7.84 (m, 2H), 7.26 (s, 1H), 7.04-7.12 (m,6H), 5.85 (m, 1H), 4.94-4.98 (m, 1H), 4.14-4.18 (m, 1H), 4.02-4.06 (m,2H), 3.31 (m, 1H), 3.15 (d, J=8.5 Hz, 3H), 3.00 (d, J=5.0 Hz, 3H),2.07-1.73 (d, J=6.5 Hz, 3H) ppm. Compound 15-15 was separated into apair of enantiomers: enantiomer 15-15a (t_(R)=3.66 min) and enantiomer15-15b (t_(R)=4.25 min) detected by UV absorption at 214 nm on a 4.6mm×250 mm×5 μm Daicel CHIRALPAK AS-H column (column temperature: 39.7°C.; eluent: MeOH/liquid CO₂=20/80 (v/v); CO₂ flow rate: 2.4 g/min andco-solvent flow rate: 0.6 g/min; front pressure: 198 bar and backpressure: 150 bar).

Step 1. Refer to Scheme 16. To a solution of compound 16-1 (1.00 g, 7.14mmol) and SEMCl (0.670 mL, 7.14 mmol) in CH₃CN (10 mL) was slowly addedCs₂CO₃ (1.57 g, 7.86 mmol). After stirring at rt for 3 hrs, the reactionmixture was concentrated and the residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=3/1 to 1/1 (v/v)) to givecompound 16-2 (1.35 g, 70% yield) as a yellow solid. LC-MS (ESI): m/z271.1 [M+H]⁺.

Step 2. To a solution of compound 16-2 (1.25 g, 4.61 mmol) in EtOH (20mL) was added 10% Pd/C (311 mg), the reaction mixture was stirred at rtovernight under an atmosphere of hydrogen. The mixture was filteredthrough Celite® 545 and the filtered cake was washed with EtOH (20mL×2). The filtrate was concentrated and the residue was dried in vacuoto give compound 16-3 (1.10 g, 99% yield) as a yellow oil. LC-MS (ESI):m/z 241.1 [M+H]⁺.

Step 3. To a solution of compound 16-3 (1.10 g, 4.58 mmol) and Et₃N(3.72 mL, 26.7 mmol) in DCM (15 mL) was added drop-wise a solution ofMsCl (0.63 mL, 8.0 mmol) in DCM (30 mL) over 30 min at 0° C. Afterstirring at rt overnight, the reaction mixture was filtered throughCelite® 545 and the filtered cake was washed with DCM (30 mL×2). Thefiltrate was concentrated and the residue was dried in vacuo to give amixture of compounds 16-4 and 16-4′ (2.30 g) as a yellow oil, which wasused directly for next step without further purification. LC-MS (ESI):m/z 319.1 [M+H]⁺ and 397.1 [M+H]⁺ for compounds 16-4 and 16-4′,respectively.

Step 4. To a solution of compounds 16-4 and 16-4′ (2.30 g, 5.81 mmol) inDMF (20 mL) and H₂O (4 mL) were added K₂CO₃ (2.94 g, 21.3 mmol) and5-bromopent-1-ene (1.31 g, 8.83 mmol) at rt. After stirring at 80° C.for 3 hrs, the reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (Petroleumether/Acetone=4/1 to 1/1 (v/v)) to give compound 16-5 (1.60 g, 90%yield, two steps from compound 16-3) as a white solid. LC-MS (ESI): m/z387.2 [M+H]⁺.

Step 5. To a solution of compound 16-5 (1.15 g, 2.98 mmol) in THF (25mL) was added tetrabutylammonium fluoride (TBAF) (2.33 g, 8.93 mmol) atrt. After stirring at 45° C. overnight, the reaction mixture wasconcentrated and the residue was purified by silica gel columnchromatography (Petroleum ether/Acetone=3/1 tot/1 (v/v)) to givecompound 16-6 (564 mg, 74% yield) as a white solid. LC-MS (ESI): m/z257.1 [M+H]⁺.

Step 6. To a solution of compound 16-6 (564 mg, 2.20 mmol) in DMF (30mL) was added PBr₃ (1.77 g, 6.61 mmol) and the resulting mixture wasstirred at rt for 30 min under an atmosphere of Ar. Subsequently, thereaction was quenched by adding sat. aq. NaHCO₃ (100 mL). The mixturewas extracted with EtOAc (100 mL×3) and the combined organic extractswere washed with water (100 mL×5) and brine (50 mL) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 16-7 (350 mg, 50% yield) as a yellowpowder. LC-MS (ESI): m/z 319.0 [M+H]⁺.

Step 7. A mixture of compound 16-7 (400 mg, 1.26 mmol), Pd(OAc)₂ (30 mg,0.13 mmol), PPh₃ (66 mg, 0.25 mmol), n-Bu₄Cl (350 mg, 1.26 mmol) andK₂CO₃ (442 mg, 3.20 mmol) in MeCN/H₂O (10 mL/1 mL) was stirred at 80° C.overnight under an atmosphere of N₂. The mixture was cooled to rt andconcentrated. The residue was purified by silica gel columnchromatography (Petroleum ether/Acetone=5/1 to 2/1 (v/v)) to givecompound 16-8 (135 mg, 45% yield) as a yellow solid. LC-MS (EST): m/z239.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.68 (s, 1H), 8.50-8.51 (d, J=5Hz, 1H), 7.23-7.24 (d, J=5 Hz, 1H), 5.35 (s, 1H), 5.27 (s, 1H), 3.79(br, 2H), 2.91 (s, 3H), 2.49-2.51 (m, 2H), 1.96-1.99 (m, 2H) ppm.

Step 8. A mixture of compound 16-8 (130 mg, 0.544 mmol) and 10% Pd/C (50mg) in MeOH (30 mL) was stirred at rt for 24 hrs under an atmosphere ofH₂. The reaction mixture was filtered through Celite® 545 and thefiltered cake was washed with MeOH (30 mL×2). The filtrate wasconcentrated and the residue was dried in vacuo to give compound 16-9(120 mg, 92% yield) as an off-white solid. LC-MS (ESI): m/z 241.1[M+H]⁺.

Step 9. To a solution of O-(mesitylsulfonyl)hydroxylamine (MSH) (0.498mmol) in DCM (10 mL) was added compound 16-9 (120 mg, 0.498 mmol). Afterstirring at rt overnight, the reaction mixture was concentrated and theresidue was dried in vacuo to give crude compound 16-10 as a pale-yellowsolid, which was used directly for the next reaction without furtherpurification. LC-MS (ESI): m/z 257.1 [M+H]⁺.

Step 10. To a solution of compounds 16-10 (0.50 mmol) and 16-11 (128 mg,0.50 mmol) in DMF (6 mL) was added K₂CO₃ (275 mg, 2.0 mmol) in oneportion. After stirring at rt for 24 hrs, the reaction mixture wasconcentrated and the residue was partitioned between EtOAc (100 mL) andwater (100 mL). The organic layer was washed with water (50 mL×3) andbrine (50 mL) and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was purified by silica gel column chromatography(Petroleum ether/Acetone=10/1 to 6/1 (v/v)) to give compound 16-12 (90mg, 35% yield) as a yellow solid. LC-MS (ESI): m/z 506.1 [M+H]⁺.

Step 11. To a mixture of compound 16-12 (80 mg, 0.16 mmol) in MeOH (1mL) and THF (2 mL) was added aq. LiOH (2.0 M, 1.3 mmol). After stirringat 70° C. for 24 hrs, the mixture was cooled to rt and adjusted its pHvalue to 5-6 by adding 2 M aq. HCl. Subsequently, H₂O (30 mL) was addedand the resulting mixture was extracted with DCM (50 mL×3). The combinedorganic extracts were washed with water (50 mL×2) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 16-13 (80 mg) as a yellow solid, which wasused directly for the next step without further purification. LC-MS(ESI): m/z 478.0 [M+H]⁺.

Step 12. To a solution of compound 16-13 (80 mg, 0.16 mmol) in DMF (2mL) was added HATU (71 mg, 0.19 mmol). After stirring at rt for 10 min,to the reaction mixture was added Et₃N (81 mg, 0.80 mmol), followed byMeNH₂.HCl (13 mg, 0.19 mmol). The resulting mixture was stirred at rtfor 30 min and then partitioned between EtOAc (25 mL) and water (25 mL).The organic layer was isolated, washed with water (25 mL×3) and brine(25 mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (Petroleumether/Acetone=10/1 to 6/1 (v/v)) to give compound 16-14 (65 mg, 83%yield) as a yellow solid. LC-MS (ESI): m/z 491.1 [M+H]⁺; ¹H NMR (500MHz, CDCl₃): δ 8.53 (s, 1H), 8.21 (s, 1H), 7.68 (dd, J₁=2.0 Hz, J₂=6.8Hz, 2H), 7.57 (dd, J_(j)=1.5 Hz, J₂=6.5 Hz, 2H), 5.51 (m, 1H), 4.18 (m,1H), 3.23 (m, 2H), 3.11 (s, 3H), 2.89 (d, J=5.0 Hz, 3H), 1.99-2.09 (m,2H), 1.81 (m, 2H), 1.50 (d, J=7.0 Hz, 3H) ppm.

Step 13. A mixture of compound 16-14 (60.0 mg, 0.122 mmol),4-fluorophenol (16.4 mg, 0.146 mmol), Pd(OAc)₂ (2.7 mg, 0.012 mmol),t-BuXphos (2.6 mg, 0.0061 mmol) and K₃PO₄ (51.7 mg, 0.244 mmol) intoluene (4 mL) was stirred at 80° C. for 4 hrs under an atmosphere ofN₂. The mixture was concentrated and the residue was diluted with EtOAc(25 mL) and filtered through Celite® 545. The filtrate was concentratedand the residue was purified by preparative HPLC to give compound 16-15(13 mg, 20% yield) as a white solid. LC-MS (ESI): m/z 523.2 [M+H]⁺; ¹HNMR (500 MHz, CDCl₃): δ 8.46 (s, 1H), 8.19 (s, 1H), 7.61-7.63 (m, 2H),7.58-7.60 (m, 6H), 7.19-7.49 (m, 3H), 5.50-5.51 (d, J=5.0 Hz, 1H), 4.11(br, 1H), 3.14-3.17 (m, 2H), 3.03 (s, 3H), 2.76-2.77 (d, J=5.0 Hz, 3H),1.99 (m, 2H), 1.72-1.91 (m, 2H), 1.42-1.44 (d, J=7.0 Hz, 3H) ppm.

Syntheses of Analogs of Compound 16-15. Following the same procedure asdescribed in Step 12 and replacing 4-fluorophenol with the respectivesubstituted phenols (ArOH), the following analogs of compound 16-15 wereobtained.

¹H NMR (500 MHz, CDCl₃) ArOH Target Compound [M + H]⁺ (δ, ppm)

505.2 8.45 (s, 1H), 8.16 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.33 (t, J =8.0 Hz, 2H), 7.02-7.13 (m, 5H), 5.58 (m, 1H), 4.12 (m, 1H), 3.13 (m,2H), 3.03 (s, 3H), 2.80 (d, J = 5.0 Hz, 3H), 1.89-2.02 (m, 2H), 1.71 (m,2H), 1.42 (d, J = 7.0 Hz, 3H)

539.1 8.45 (s, 1H), 8.16 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.44 (d, J =1.5 Hz, 1H), 7.01-7.23 (m, 5H), 5.56 (m, 1H), 4.10 (m, 1H), 3.14 (m,2H), 3.03 (s, 3H), 2.79 (d, J = 4.5 Hz, 3H), 1.96 (m, 2H), 1.72 (m, 2H),1.44 (d, J = 6.5 Hz, 3H)

523.2 8.51 (s, 1H), 8.23 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.17-7.23(m, 4H), 7.11 (d, J = 8.5 Hz, 2H), 5.63 (m, 1H), 4.21 (m, 1H), 3.21 (m,2H), 3.10 (s, 3H), 2.86 (d, J = 5.0 Hz, 3H), 1.96 (m, 2H), 1.79 (m, 2H),1.49 (d, J = 6.5 Hz, 3H)

523.2 8.45 (s, 1H), 8.15 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.26 (m,1H), 7.10 (d, J = 8.5 Hz, 2H), 6.79 (m, 2H), 6.73 (dd, J₁ = 2.0 Hz, J₂ =10.3 Hz, 1H), 5.54 (m, 1H), 4.12 (m, 1H), 3.14 (m, 2H), 3.30 (s, 3H),2.81 (d, J = 4.5 Hz, 3H), 1.91-1.99 (m, 2H), 1.71 (m, 1H), 1.51 (m 1H),1.42 (d, J = 7.0 Hz, 3H)

541.2 8.52 (s, 1H), 8.22 (s, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.18 (dd, J₁= 9.0 Hz, J₂ = 18.5 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 6.89 (m, 1H),6.82 (m, 1H), 5.61 (m, 1H), 4.17 (m, 1H), 3.21 (m, 2H), 3.10 (s, 3H),2.88 (d, J = 4.5 Hz, 3H), 2.03- 2.08 (m, 2H), 1.98 (m, 1H), 1.59 (m,1H), 1.49 (d, J = 7.0 Hz, 3H)

539.1 8.45 (s, 1H), 8.16 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.24 (t, J =7.5 Hz, 1H), 7.07-7.10 (m, 3H), 7.00 (t, J = 2.5 Hz, 1H), 6.91 (dd, J₁ =2.0 Hz, J₂ = 8.0 Hz, 1H), 5.55 (m, 1H), 4.13 (m, 1H), 3.14 (m, 2H), 3.30(s, 3H), 2.81 (d, J = 5.0 Hz, 3H), 1.91-1.98 (m, 2H), 1.71 (m, 1H), 1.51(m, 1H), 1.42 (d, J = 7.0 Hz, 3H)

539.1 8.44 (s, 1H), 8.15 (s, 1H), 7.57 (d, J = 9.0 Hz, 2H), 7.29 (m,2H), 7.06 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 5.55 (m, 1H),4.11 (m, 1H), 3.14 (m, 2H), 3.30 (s, 3H), 2.80 (d, J = 5.0 Hz, 3H),1.93-2.00 (m, 2H), 1.72 (m, 1H), 1.51 (m, 1H), 1.42 (d, J = 7.0 Hz, 3H)

Synthesis of Compound 16-16. Compound 16-16 was obtained as a whitesolid from the hydrogenation of compound 16-14 in the presence of 5%Pd/C in EtOH. LC-MS (ESI): m/z 413.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ8.45 (s, 1H), 8.19 (s, 1H), 7.58-7.59 (m, 2H), 7.45-7.49 (m, 3H), 5.51(m 1H), 4.11 (m, 1H), 3.16 (m, 2H), 3.14 (s, 3H), 2.76 (d, J=4.5 Hz,3H), 1.90-1.99 (m, 2H), 1.73 (m, 1H), 1.48 (m, 1H), 1.43 (d, J=6.5 Hz,3H) ppm.

Step 1. Refer to Scheme 17. A mixture of compound 17-1 (100 mg, 0.225mmol) (readily prepared by onzonlysis of compound 6-5), paraformaldehyde(20 mg, 0.67 mmol) and morpholine (2 μL, 0.02 mmol) in acetic acid (2mL) was heated at 120° C. for 2 hrs under an atmosphere of N₂. Thereaction mixture was concentrated and the residue was dissolved inTHF/EtOH (10 mL/10 mL) and PtO₂ (22 mg) was added. After stirring at rtovernight under an atmosphere of H₂, the reaction mixture was filteredthrough Celite® 545 and the filtered cake was washed with EtOH (20mL×2). The filtrate was concentrated and the residue was purified bysilica gel column chromatography (Petroleum ether/EtOAc=4/1 (v/v)) togive compound 17-3 (45 mg, 33% yield, two steps from 17-1) as a whitesolid. LC-MS (ESI): m/z 460.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.40(s, 1H), 8.12 (m, 2H), 7.71 (s, 1H), 7.20 (m, 2H), 4.45 (q, J=7.0 Hz,2H), 4.15 (m, 1H), 3.62 (m, 1H), 3.07 (s+m, 3+1H), 2.33 (m, 1H), 1.79(m, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.32 (d, J=7.0 Hz, 3H) ppm.

Step 2. A mixture of compound 17-3 (182 mg, 0.396 mmol) and LiOH (50 mg,1.19 mmol) in THF (20 mL), MeOH (5 mL), and water (5 mL) was refluxedand monitored by LC-MS. After the reaction went completion, the reactionmixture was cooled to 0° C. and adjusted its pH value to 7 by adding 1 Maq. HCl. The organic solvent was removed and the residue was trituratedwith water (15 mL) and then filtered. The solid was washed with water(10 mL×3) and dried in vacuo to give compound 17-4, which was used inthe next step without further purification. LC-MS (ESI): m/z 432.1[M+H]⁺.

Step 3. To a solution of compound 17-4 (about 0.396 mmol, crude) andHATU (181 mg, 0.475 mmol) in DMF (4 mL) was added DIPEA (131 μL, 0.792mmol). After stirring at rt for 15 min, the mixture was added to DIPEA(196 μL, 1.19 mmol), followed by methylamine hydrochloride (80 mg, 1.19mmol) and the resulting mixture was stirred at rt for 2 hrs.Subsequently, the mixture was concentrated and the residue was dilutedwith water and filtered. The solid was collected and purified bypreparative HPLC to give compound 17-5 as a white solid. LC-MS (ESI):m/z 445.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.13 (s, 1H), 8.00 (m, 2H),7.21 (m, 2H), 7.71 (s, 1H), 5.90 (brs, 1H), 4.15 (m, 1H), 3.64 (m, 1H),3.08 (s, 3H), 3.05 (d, J=5.0 Hz, 3H), 3.03 (m, 1H), 2.32 (m, 1H), 1.80(m, 1H), 1.32 (d, J=6.5 Hz, 3H) ppm.

Step 4. To a solution of compound 17-5 (40 mg, 0.090 mmol) in MeOH (4mL) was added NaBH₄ (10 mg, 0.27 mmol) at 0° C. After stirring at 0° C.for 30 min, the reaction was quenched by adding several drops ofacetone. The solvent was removed and the residue was diluted with water(25 mL) and extracted with DCM (25 mL×2). The combined organic extractswere washed with brine (25 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by preparative HPLC togive compound 17-6 as a white solid and as a mixture of cis- andtrans-isomers. LC-MS (ESI): m/z 447.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃,major isomer): δ 7.93 (s, 2H), 7.87 (s, 1H), 7.58 (s, 1H), 7.20 (m, 2H),5.93 (brs, 1H), 4.78 (d, J=7.0 Hz, 1H), 3.70 (m, 1H), 3.11 (s, 3H), 3.02(d, J=5.0 Hz, 3H), 2.08 (brs, 1H), 1.61 (brs, 1H), 1.03 (brs, 3H) ppm.

Step 5. A mixture of compound 17-6 (88 mg, 0.20 mmol) and TsOH (8 mg,0.04 mmol) in toluene (6 mL) was refluxed for 2 hrs under an atmosphereof N₂. The solvent was removed and the residue was purified bypreparative HPLC to give compound 17-7 as a white solid. LC-MS (ESI):m/z 429.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.90 (m, 2H), 7.71 (m, 1H),7.67 (s, 1H), 7.19 (m, 2H), 6.44 (s, 1H), 5.81 (brs, 1H), 3.87 (brs,2H), 3.01 (d, J=5.0 Hz, 3H), 2.74 (s, 3H), 2.68 (m, 2H), 2.00 (s, 3H)ppm.

Step 6. A mixture of compound 17-7 (56 mg, 0.13 mmol) and PtO₂ (23 mg)in THF (4 mL) and MeOH (4 mL) was stirred at rt overnight under anatmosphere of H₂. The mixture was filtered through Celite® 545 and thefiltered cake was washed with MeOH (25 mL×2). The filtrate wasconcentrated and the residue was purified by preparative HPLC to givecompound 17-8 as a white solid. LC-MS (ESI): m/z 431.1 [M+H]⁺; ¹H NMR(500 MHz, CDCl₃): δ 7.90 (s, 2H), 7.67 (s, 1H), 7.58 (s, 1H), 7.19 (m,2H), 5.79 (brs, 1H), 4.10 (brs, 1H), 3.31 (brs, 1H), 3.06 (s, 3H), 3.01(d, J=5.0 Hz, 3H), 2.87 (m, 2H), 1.68-1.90 (m, 3H), 1.04 (d, J=6.0 Hz,3H) ppm.

Step 1. Refer to Scheme 18. A solution of compound 8-4 (656 mg, 1.57mmol) and aminopropene (3.70 mL, 50.0 mmol) in THF (dry) was slowlyadded Ti(O^(i)Pr)₄ (16.5 mL, 20.0 mmol) and the resulting mixture wasstirred at rt for 4 hrs. Subsequently, EtOH (30 mL) and NaBH₄ (760 mg,20.0 mmol) were added and the mixture was stirred at rt overnight.Subsequently, the mixture was poured into ice-water (100 mL) and thesuspension was filtered. The filtrate was concentrated and the residuewas diluted with EtOAc (200 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=6/1 (v/v)) to give compound 18-1(7.0 g, 87% yield) as a yellow solid. LC-MS (ESI): m/z 459.2 [M+H]⁺.

Step 2. To a solution of compound 18-1 in anhydrous DCM (30 mL) wasadded NaH (172 mg, 43.0 mmol) at 0° C. After stirring at 0° C. for 30min, compound 8-6 (640 mg, 1.44 mmol) was added and the resultingmixture was stirred at 0° C. for 3 hrs and at rt overnight.Subsequently, sat. aq. NH₄Cl (10 mL) was added and the aqueous phase wasextracted with DCM (25 mL×3). The combined organic extracts were washedwith brine (25 mL) and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/EtOAc=6/1 (v/v)) to give compound 18-2 (200 mg, 71%yield) as a white solid. LC-MS (ESI): m/z 487.1 [M+H]⁺.

Step 3. To a solution of compound 18-2 (100 mg, 0.100 mmol) in MeOH/THF(1 mL/2 mL) was added aq. LiOH (2.0 M, 0.5 mL). After stirring at 80° C.for 12 hrs, the reaction mixture was acidified to pH 2-3 by adding aq.HCl (2.0 M), and then concentrated. The residue was dissolved in EtOAc(25 mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give crude acid, which was used in thenext step without further purification. LC-MS (ESI): m/z 459.1 [M+H]⁺.Subsequently, the crude acid was dissolved in DMF (3 mL) and HATU (74mg, 0.25 mmol) was added. The mixture was stirred at rt for 1 hr andthen DIPEA (0.40 mL, 2.02 mmol) and MeNH₂.HCl (82 mg, 1.2 mmol) wereadded. After stirring at rt for 1 hr, the reaction mixture wasconcentrated and the residue was diluted with EtOAc (50 mL). Thesolution was washed with brine (25 mL) and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (Petroleum ether/EtOAc=5/1 (v/v)) to give compound18-3 (70 mg, 55% yield) as a white solid. LC-MS (ESI): m/z 472.1 [M+H]⁺.

Step 4. To a solution of compound 18-3 (42 mg) in THF (1 mL) were addedpolymethylhydrosiloxane (PMHS) (0.18 mmol), ZnCl₂ (3.0 mg, 0.02 mmol)and Pd[PPh₃]₄ (1.04 mg, 0.009 mmol), the mixture was stirred at 25° C.for 12 hrs under an atmosphere of N₂. The solvent was removed and theresidue was purified by preparative HPLC to give compound 18-5 (9 mg,23% yield) as a white solid. LC-MS (ESI): m/z 432.1 [M+H]⁺; ¹H NMR (500MHz, d⁶-DMSO): δ 8.49 (m, 1H), 7.94 (dd, J₁=5.0 Hz, J₂=8.3 Hz, 2H), 7.74(s, 1H), 7.50 (s, 1H), 7.39 (t, J=9.0 Hz, 2H), 4.13 (m, 1H), 3.25 (m,5H), 3.04 (m, 2H), 2.84 (d, J=4.5 Hz, 3H), 1.49 (d, J=6.5 Hz, 3H) ppm.

Synthesis of Compound 18-4. Following the same procedure as described inStep 4 and replacing compound 18-3 with 18-2, compound 18-4 wasobtained. LC-MS (ESI): m/z 447.1 [M+H]⁺.

Synthesis of Compound 18-6. Method A. To a solution of compound 18-4(120 mg, 0.248 mmol) and NaHCO₃ (42 mg, 0.50 mmol) in DMF (3 mL) wasadded CF₃CH₂OTf (69 mg, 0.30 mmol). The resulting mixture was stirred atrt overnight. The solvent was removed and the residue was diluted withEtOAc (50 mL). The mixture was washed with brine (25 mL) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give an ester, LC-MS (ESI): m/z 529.1 [M+H]⁺, which wassubsequently hydrolyzed and performed methyl amide formation, followingthe conditions described in Step 3, to give compound 18-6. LC-MS (ESI):m/z 514.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.51 (m, 1H), 7.97 (m,2H), 7.80 (s, 1H), 7.58 (s, 1H), 7.40 (m, 2H), 4.44 (m, 1H), 3.85 (m,1H), 3.33-3.38 (m, 6H), 2.99 (m, 2H), 2.86 (d, J=5.0 Hz, 3H), 1.51 (d,J=5.5 Hz, 3H) ppm.

Synthesis of Compound 18-7. Method B. To a solution of compound 18-4(100 mg, 0.224 mmol) and pyridine (106 mg, 1.34 mmol) in DCM (5 mL) wasadded methyl chloroformate (37 mg, 0.47 mmol) at 0° C. and the resultingmixture was stirred at rt for 30 min. The reaction was quenched byadding several drops of sat. aq. NaHCO₃ and the mixture wasconcentrated. The residue was diluted with DCM (60 mL) and the mixturewas washed with brine (25 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was dried in vacuo to give an ester,LC-MS (ESI): m/z 505.1 [M+H]⁺, which was subsequently hydrolyzed andperformed methyl amide formation, following the conditions described inStep 3, to give compound 18-7. LC-MS (ESI): m/z 490.1 [M+H]⁺; ¹H NMR(500 MHz, CD₃CN): δ 7.96 (m, 2H), 7.71 (s, 1H), 7.55 (s, 1H), 7.28 (m,2H), 6.78 (br, 1H), 5.45-5.54 (m, 1H), 4.14 (m, 2H), 3.99-4.04 (m, 4H),3.24-3.28 (m, 4H), 2.91 (d, J=4.5 Hz, 3H), 1.68 (br, 3H) ppm.

Synthesis of Compound 18-8. Method C. To a solution of compound 18-4 (70mg, 0.16 mmol) in MeOH (5 mL) were added 37% aq. HCHO (0.050 mL, 0.63mmol) and HOAc (0.020 mL, 0.31 mmol). The reaction mixture was stirredat 40° C. for 2 hrs and then cooled to rt. Subsequently, NaBH₄ (50 mg,0.79 mmol) was slowly added and the mixture was stirred at rt for 30min. The solvent was removed and the residue was diluted with EtOAc (25mL). The mixture was washed with brine (10 mL) and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive a crude ester (70 mg) as a yellow solid, LC-MS: (ESI) m/z 461.1[M+H]⁺, which was subsequently hydrolyzed and performed methyl amideformation, following the conditions described in Step 3, to givecompound 18-8. LC-MS (ESI): m/z 446.1 [M+H]⁺; ¹H NMR (300 MHz, d⁶-DMSO):δ 7.92 (m, 2H), 7.66 (s, 1H), 7.49 (s, 1H), 7.33 (m, 2H), 4.20 (m, 1H),3.50-3.53 (m, 2H), 3.42 (br, 3H), 3.29-3.30 (m, 2H), 2.84 (d, J=4.5 Hz,3H), 2.10 (br, 3H), 1.49 (d, J=7.2 Hz, 3H) ppm.

Synthesis of Compound 18-9. Following the same procedure as described inMethod C and replacing 37% aq. HCHO with(1-ethoxycyclopropoxy)trimethylsilane, compound 18-9 was obtained. LC-MS(ESI): m/z 472.1 [M+H]⁺.

Synthesis of Compound 18-10. Following the same procedure as describedin Method C and replacing 37% aq. HCHO with cyclopropanecarbaldehyde,compound 18-10 was obtained. LC-MS (ESI): m/z 486.2 [M+H]⁺.

Step 1. Refer to Scheme 18a. To a solution of compound 8-4 (2.1 g, 5mmol) in dry THF (20 mL) was added MeNH₂ (2 M in THF, 20 mL, 40 mmol),followed by Ti(O^(i)Pr)₄ (6 mL, 20 mmol) under an atmosphere of N₂.After stirring at rt overnight, the reaction mixture was cooled to 0° C.and sequentially added EtOH (20 mL) and NaBH₄ (945 mg, 25 mmol). Thereaction mixture was stirred at 0° C. for 2 hrs and slowly added H₂O (20mL). The suspension was filtered and the filtrate was extracted with DCM(100 mL×3). The combined organic extracts were washed with brine (50 mL)and dried over anhydrous Na₂SO₄. The solvent was removed and the residuewas dried in vacuo to give crude compound 18a-2a (2.17 g) as a yellowsolid, which was used directly for the next step without furtherpurification. LC-MS (ESI): m/z 435.1 [M+H]⁺.

Step 2. To a solution of compound 18a-2a (2.17 g, 5.0 mmol) in DCM (40mL) at 0° C. was added anhydrous pyridine (0.8 mL, 10 mmol), followed by2-chloroacetyl chloride (0.75 mL, 10 mmol). After stirring at 0° C. for2 hrs, the reaction mixture was warmed to rt and treated with 1 M aq.HCl (10 mL). The mixture was extracted with EtOAc (100 mL×3) and thecombined organic extracts were washed with H₂O (50 mL) and brine (50 mL)and dried over anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by silica gel column chromatography (PE/EtOAc=1/1 (v/v)) togive compound 18a-3a (1.8 g, 71% yield) as a light yellow solid. LC-MS(ESI): m/z 511.1 [M+H]⁺.

Step 3. To a solution of compound 18a-3a (2.55 g, 5.0 mmol) in toluene(50 mL) was added K₂CO₃ (1.38 g, 10 mmol). After stirring at 80° C.stirred for 4 hrs, the reaction mixture was cooled to rt and filtered.The filtrate was concentrated and the residue was dried in vacuo to givecrude compound 18a-4a (2.4 g) as a yellow solid, which was used for thenext step without further purification. LC-MS (ESI): m/z 475.1 [M+H]⁺.

Step 4. Following the same procedure as that for the preparation ofcompound 18-3 described in Scheme 18 and replacing compound 18-2 with18a-4a, compound 18a-5a (1.1 g, 57% yield) was obtained as a whitesolid. LC-MS (ESI): m/z 460.1 [M+H]⁺; ¹H NMR (500 MHz, CD₃OD): δ 7.82(br, 2H), 7.63 (s, 1H), 7.59 (s, 1H), 7.14 (t, J=7 Hz, 2H). 4.69 (q, J=6Hz, 1H), 4.59 (d, J=18 Hz, 1H), 3.96 (d, J=18 Hz, 1H), 3.27 (s, 3H),3.06 (s, 3H), 2.82 (s, 3H), 1.66 (d, J=6 Hz, 3H) ppm. Compound 18a-5awas separated into a pair of enantiomers: enantiomer 18a-5a_A(t_(R)=2.48 min) and enantiomer 18a-5a_B (t_(R)=3.28 min) detected by UVabsorption at 214 nm on a 4.6 mm×250 mm×5 μm Daicel CHIRALPAK® OD-Hcolumn (column temperature: 39.3° C.; eluent: MeOH/liquid CO₂=50/50(v/v); CO₂ flow rate: 1.5 g/min and co-solvent flow rate: 1.5 g/min;front pressure: 235 bar and back pressure: 152 bar).

Synthesis of Compound 18b-2b. Following the same procedure as that forthe synthesis of compound 18a-2a described in Scheme 18a and replacingmethylamine with 2,4-dimethoxybenzylamine, compound 18a-2b (6.5 g crudeproduct) was obtained as a yellow solid. LC-MS (ESI): m/z 571.2 [M+H]⁺.

Synthesis of Compound 18b-3b. Following the same procedure as that forthe synthesis of compound 18a-3a described in Scheme 18a and replacingcompound 18a-2a with 18a-2b, compound 18a-3b (4.9 g, 75% yield) wasobtained as a light yellow solid. LC-MS (ESI): m/z 647.2 [M+H]⁺.

Synthesis of Compound 18a-4b. Following the same procedure as that forthe synthesis of compound 18a-4a described in Scheme 18a and replacingcompound 18a-3a with 18a-3b, compound 18a-4b (3.4 g crude product) wasobtained as a yellow solid. LC-MS (ESI): m/z 611.2 [M+H]⁺.

Synthesis of Compound 18a-4c. To a stirred solution of compound 18a-4b(3.4 g, 7.3 mmol) in DCM (10 mL) was added TFA (20 mL). After stirringat rt overnight, the reaction mixture was concentrated and the residuewas purified by column chromatography to give compound 18a-4c as a paleyellow solid. LC-MS (ESI): m/z 461.1 [M+H]⁺.

Synthesis of Compound 18a-5b. Following the same procedure as that forthe preparation of compound 18-3 described in Scheme 18 and replacingcompound 18-2 with 18a-4c, compound 18a-5b (700 mg, 40% yield) wasobtained as a white solid. LC-MS (ESI): m/z 446.1 [M+H]⁺; ¹H NMR (500MHz, CDCl₃): δ 7.91 (s, 1H), 7.84-7.87 (m, 2H). 7.59 (s, 1H), 7.22 (t,J=8 Hz, 2H), 5.95 (s, 1H), 5.79 (br, 1H), 5.24-5.26 (m, 1H), 4.92 (d,J=18 Hz, 1H), 3.93 (d, J=18 Hz, 1H), 3.20 (s, 3H), 2.99 (d, J=5 Hz, 3H),1.74 (d, J=7 Hz, 3H) ppm. Compound 18a-5a was separated into a pair ofenantiomers: enantiomer 18a-5b_A (t_(R)=3.67 min) and enantiomer18a-5b_B (t_(R)=4.53 min) detected by UV absorption at 214 nm on a 4.6mm×250 mm×5 μm ChiralPak® OD-H column (column temperature: 39.7° C.;eluent: MeOH/liquid CO₂=30/70 (v/v); CO₂ flow rate: 2.1 g/min andco-solvent flow rate: 0.9 g/min; front pressure: 207 bar and backpressure: 150 bar).

Step 1. Refer to Scheme 19. A mixture of compound 6-5 (1.00 g, 2.25mmol) and 5% Pd/C (1.0 g) in THF/MeOH (50 mL/50 mL) was stirred at rtovernight under an atmosphere of H₂. The mixture was filtered throughCelite® 545 and the filtered cake was washed with MeOH (25 mL×2). Thefiltrate was concentrated and the residue was dried in vacuo to givecompound 19-1 (970 mg, 97% yield). LC-MS (ESI): m/z 446.1 [M+H]⁺.

Step 2. To a solution of compound 19-1 (970 mg, 2.18 mmol) in MeOH/THF(10 mL/10 mL) was added aq. LiOH (2.0 N, 4.36 mmol, 8.72 mmol). Afterstirring at 75° C. for 2 hrs, the reaction mixture was cooled to rt andadjusted to pH 5-6 by adding aq. HCl (2.0 N). The mixture wasconcentrated and the residue was diluted with EtOAc (100 mL) and H₂O (25mL). The organic layer was dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give compound 19-2 (880mg, 96% yield) as a white solid. LC-MS (ESI): m/z 418.1 [M+H]⁺.

Step 3. To a solution of compound 19-2 (830 mg, 2.0 mmol) in DCM (50 ml)was added (COCl)₂ (379 mg, 3.0 mmol) at rt and the resulting mixture wasstirred at rt for 1 hr. Subsequently, the mixture was cooled to 0° C.and ethylenediamine was added (359 mg, 6.0 mmol). The resulting mixturewas stirred at rt for 30 min and then concentrated to give crudecompound 19-3, which was used for the next step without furtherpurification. LC-MS (ESI): m/z 460.2 [M+H]⁺.

Step 4. A solution of compound 19-3 (900 mg, 1.96 mmol) and POCl₃ (1.20g, 7.84 mmol) in toluene (30 mL) was stirred at 90° C. overnight underan atmosphere of N₂. The reaction mixture was concentrated and theresidue was added sat. aq. NaHCO₃ to adjust to pH 7-8. The resultingsuspension was filtered and the solid was dried in vacuo to give crudecompound 19-4 as a white solid. LC-MS (ESI): m/z 442.2 [M+H]⁺.

Step 5. A solution of compound 19-4 (250 mg, 0.57 mmol), PhI(OAc)₂ (201mg, 0.62 mmol) and K₂CO₃ (86 mg, 0.62 mmol) in DMSO (5 mL) was stirredat 25° C. for 24 hrs. The mixture was concentrated and the residue waspurified by preparative HPLC to give compound 19-5 (30 mg, 12% yield) asa white solid. LC-MS (ESI): m/z 440.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO):δ 12.43 (br, 1H), 7.95-7.98 (m, 2H), 7.48 (s, 1H), 7.34 (m, 3H), 7.20(s, 1H), 4.08 (br, 2H), 3.21 (s, 3H), 3.04 (s, 1H), 1.92 (br, 4H), 1.36(d, 2H, J=7.0 Hz) ppm.

Synthesis of Compound 19-6. Following the same procedure as described inthe synthesis of compound 19-5 and replacing compound 19-2 with thecorresponding de-methylated analog, compound 19-6 was obtained. LC-MS(ESI): m/z 426.1 [M+H]⁺.

Synthesis of Compound 19-7. Following the same procedure as described inthe synthesis of compound 19-5 and replacing compound 19-2 with thecorresponding de-methylated eight-member ring analog, compound 19-7 wasobtained. LC-MS (ESI): m/z 440.1 [M+H]⁺.

Synthesis of Compound 19a-2. Refer to Scheme 19a. A solution of compound19a-1 (250 mg, 0.54 mmol) (prepared from compound 8-8 by following theprocedure for the conversion of compound 19-2 to 19-3 described inScheme 19) in POCl₃ (5 mL) was stirred at 75° C. for 3 hrs under anatmosphere of N₂ and then was concentrated to remove POCl₃ under areduced pressure. Subsequently, the residue was added sat. aq. NaHCO₃(25 mL) and the resulting suspension was extracted with EtOAc (40 mL×3).The combined organic extracts were washed with brine (50 mL) dried overanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give crude compound 19a-2 (100 mg) as a white solid, which wasused for the next aromatization step without further purification. LC-MS(ESI): m/z 444.1 [M+H]⁺.

Synthesis of Compound 19-8. Following the same procedure as described inthe preparation of compound 19-5 described in Scheme 19 and replacingcompound 19-4 with 19a-2, compound 19-8 was obtained. LC-MS (ESI): m/z442.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 12.46 (d, J=10 Hz, 1H),8.01-8.03 (m, 2H), 7.85 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.33-7.37 (m,3H), 7.20 (s, 1H), 4.87-4.88 (m, 1H), 3.87-4.06 (m, 4H), 3.38 (s, 3H),1.59 (d, J=7.0 Hz, 3H) ppm.

Synthesis of Compound 19-9. Following the same procedure as described inthe preparation of compound 19-5 described in Scheme 19, replacingcompound 19-2 with 15-14, and taking the modified condition fordihydroimidazole formation shown in Scheme 19a, compound 19-8 wasobtained. LC-MS (ESI): m/z 534.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ12.46 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 7.60 (s, 1H), 7.36(s, 1H), 7.26-7.30 (m, 2H), 7.15-7.19 (m, 3H), 7.06 (d, J=8.5 Hz, 2H),4.87 (m, 1H), 4.00-4.03 (m, 1H), 3.88-3.93 (m, 2H), 3.38 (s, 3H),3.18-3.19 (m, 1H), 1.58 (d, J=6.5 Hz, 3H) ppm.

Synthesis of Compound 19-10. Following the same procedure as describedin the preparation of compound 19-5 described in Scheme 19, replacingcompound 19-2 with the full carbon analog of compound 15-14 (preparedfrom compound 23-6 shown in Scheme 23 by hydrogenation of the terminalalkene residue and hydrolysis of the ethyl ester moiety), and taking themodified condition for dihydroimidazole formation shown in Scheme 19a,compound 19-10 was obtained. LC-MS (ESI): m/z 532.2 [M+H]⁺.

Step 1. Refer to Scheme 20. To a solution of compound 4-4 (1.0 g, 2.5mmol), DMAP (20 mg), and anhydrous pyridine (1.98 g, 25.0 mmol) inCH₂Cl₂ (20 mL) MsCl was added drop wise (0.86 g, 7.6 mmol) at 0° C.After stirring at rt for 2 hrs, ice-water was added to the reactionmixture (100 mL). The organic layer was washed with water (20 mL) andbrine (20 mL) and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was purified by silica gel column chromatography(Petroleum ether/Acetone=4/1 (v/v)) to give compound 20-1 (1.15 g, 96%yield). LC-MS (ESI): m/z 476.1 [M+H]⁺.

Step 2. A mixture of compound 20-1 (1.1 g, 2.3 mmol) and 10% Pd/C (1.1g) in EtOAc (100 mL) was stirred at rt overnight under an atmosphere ofH₂. The mixture was filtered through Celite® 545 and the filtered cakewas washed with EtOAc (25 mL×2). The filtrate was concentrated and theresidue was dried in vacuo to give compound 20-2 (1.0 g, 98% yield).LC-MS (ESI): m/z 450.1 [M+H]⁺.

Step 3. To a solution of compound 20-2 (1.00 g, 2.23 mmol) in THF (35mL) was added DIPEA (7 mL) and the resulting mixture was refluxedovernight. The solvent was removed and the residue was dried in vacuo togive crude compound 20-3 (760 mg, 78% yield) as a yellow solid. LC-MS(ESI): m/z 354.1 [M+H]⁺.

Step 4. A solution of chlorosulfonyl isocyanate (0.3 mL, 3.4 mmol) inanhydrous DCM (3 mL) was added drop wise to tert-butanol (0.3 mL, 3.4mmol) at 0° C. and the resulting mixture was stirred at rt for 2 hrs.Subsequently, the mixture was cooled to 0° C. and a solution of compound20-3 (60 mg, 0.17 mmol) and TEA (0.6 mL) in anhydrous DCM (3 mL) wasadded drop wise. After stirring at rt for 3 hrs, the reaction mixturewas diluted with water (10 mL) and DCM (20 mL). The organic layer waswashed with brine and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was dried in vacuo to give crude compound 20-4(70 mg, 77% yield) as a yellow solid. LC-MS (ESI): m/z 477.1[M-C₄H₉+H]⁺.

Step 5. A mixture of compound 20-4 (70 mg, 0.13 mmol) and LiOH.H₂O (28mg, 0.66 mmol) in EtOH/THF/H₂O (1.5 mL/3 mL/1.5 mL) was stirred at 70°C. for 2 hrs. Subsequently, the mixture was added 2 N aq. HCl to adjustthe pH value to 3 and the resulting suspension was filtered. The solidwas washed with water and dried in vacuo to give compound 20-5 (60 mg,90% yield) as a yellow solid. LC-MS (ESI): m/z 449.1 [M-C₄H₉+H]⁺.

Step 6. To a solution of compound 20-5 (60 mg, 0.12 mmol) in DMF (2 mL)was added HATU (90 mg, 0.24 mmol). The resulting mixture was stirred atrt for 1 hr before DIPEA (154 mg, 1.19 mmol) and MeNH₂.HCl (40 mg, 0.60mmol) were added. After stirring at rt for 1 hr, the reaction mixturewas added into ice-water (30 mL) and the resulting suspension wasfiltered. The solid was washed with water and dried in vacuo to givecrude compound 20-6 (60 mg, 97% yield). LC-MS (ESI): m/z 462.1[M-C₄H₉+H]⁺.

Step 7. To a solution of compound 20-6 (60 mg, 0.12 mmol) in MeOH (1 mL)was added 3.5 M HCl in dioxane (20 mL). After stirring at rt overnight,the mixture was concentrated and the residue was purified by preparativeHPLC to give compound 20-7 (35 mg, 72% yield). LC-MS (ESI): m/z 418.1[M+H]⁺; ¹H NMR (500 MHz, MeOD): δ 7.95-7.92 (m, 2H), 7.73 (s, 1H), 7.52(s, 1H), 7.26 (t, J=9.0 Hz, 2H), 3.63 (br, 2H), 3.05 (s, 2H), 2.97 (s,3H), 1.96 (d, J=6.5 Hz, 2H), 1.76 (br, 2H) ppm.

Syntheses of Analogs of Compound 20-7. Following the same syntheticstrategy by treating compound 20-3 with various acyl chlorides orsulfonyl chlorides instead of chlorosulfonyl isocyanate, followed byhydrolyzation and methyl amide formation, the following analogs ofcompound 20-7 were obtained.

RCOCl ¹H NMR (500 MHz, CDCl₃) or RSO2Cl Target [M + H]⁺ (δ, ppm) MeOCOCl

397.1 7.91 (d, J = 5.5 Hz, 2H), 7.63 (s, 1H), 7.31 (s, 1H), 7.18 (t, J =5.5 Hz, 2H), 5.81 (br s, 1H), 4.46 (t, J = 2.5 Hz, 1H), 3.82 (s, 1H),3.67 (s, 2H), 3.01 (d, J = 4.5 Hz, 3H), 2.79 (t, J = 1.5 Hz, 2H),2.02-1.74 (m, 3H), 1.37 (br s, 1H) CH₃COCl

381.2 7.93-7.90 (m, 2H), 7.72 (s, 1H), 7.30 (s, 1H), 7.22-7.17 (m, 2H),5.82 (br, 1H), 4.73 (d, J = 13 Hz, 1H), 3.02 (t, J = 5 Hz, 3H),2.88-2.80 (m, 2H), 2.70- 2.65 (m, 1H), 2.05-2.00 (m, 2H), 1.90 (s, 3H),1.80-1.77 (m, 1H), 1.45-1.27 (m, 1H) Me₂NSO₂Cl

446.1 8.53 (br s, 1H), 7.96-7.94 (m, 2H), 7.62 (s, 1H), 7.54 (s, 1H),7.28-7.25 (m, 2H), 3.62-3.58 (m, 2H), 3.08 (s, 2H), 3.02 (s, 3H), 2.90(s, 5H), 1.95 (br s, 2H), 1.71 (br s, 2H) c-PrSO₂Cl

443.2 7.92-7.88 (m, 2H), 7.66 (s, 1H), 7.64 (s, 1H), 7.21-7.16 (m, 2H),5.82 (br, 1H), 3.67 (br, 2H), 3.02 (d, J = 12 Hz, 2H), 3.00 (s, 3H),2.54-2.49 (m, 2H), 1.94 (d, J = 5.5 Hz, 2H), 1.74 (br s, 2H), 1.12 (d, J= 4.0 Hz, 2H), 0.99-0.98 (m, 2H)

Step 1. Refer to Scheme 21. To a solution of compound 8-3 (600 mg, 1.76mmol) in MeOH (150 mL) were added (S)-tert-butyl2-formylpyrrolidine-1-carboxylate (1.05 g, 5.27 mmol) and glacial AcOH(106 mg, 1.76 mmol). After stirring at 35° C. for 2 hrs, the mixture wascooled to 0° C. and NaCNBH₃ (220 mg, 3.52 mmol) was added. Subsequently,the mixture was refluxed for 2 hrs and concentrated. The residue wasdissolved in EtOAc (100 mL) and the solution was washed with H₂O (50mL×3) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by reverse phase preparative HPLC to give compound21-1 (630 mg, 68% yield) as yellow fluffy solid. LC-MS (ESI): m/z 525.2[M+H]⁺.

Step 2. To a solution of compound 21-1 (600 mg, 1.15 mmol) in dioxane(10 mL) was added 4 N HCl in dioxane (20 mL). After stirring at 35° C.for 2 hrs, the reaction mixture was concentrated and the residue wasdried in vacuo to give crude compound 21-2 (500 mg, quantitative yield)as a yellow solid. LC-MS (ESI): m/z 425.2 [M+H]⁺.

Step 3. To a stirred solution of compound 21-2 (500 mg, 1.2 mmol) inEtOH (30 mL) was added 1 N HCl in dioxane (2 mL). After stirring at 35°C. for 2 hrs, the reaction mixture was cooled to 0° C. and NaCNBH₃ (148mg, 2.4 mmol) was added. The mixture was stirred at rt for 2 hrs andconcentrated. The residue was dissolved in EtOAc (100 mL) and thesolution was washed with brine (25 mL) and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was purified by reverse phasepreparative HPLC to give compound 21-3 (420 mg, 87% yield) as a yellowfoam. LC-MS (ESI): m/z 409.2 [M+H]⁺. Long column (30 min) HPLC andChiral HPLC showed there was only one diastereomer formed during thereductive-elimination step; however, the chirality of the benzyliccarbon in compound 21-3 was not determined.

Step 4. To a solution of compound 21-3 (300 mg, 0.73 mmol) and Et₃N (0.3mL) in DCM (30 mL) was added MsCl drop wise (85 mg, 0.73 mmol) at 0° C.After stirring at rt for 30 min, the reaction mixture was washed withH₂O (20 mL×3) and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was purified by reverse phase preparative HPLC to givecompound 21-4 (186 mg, 52% yield) as a yellow solid. LC-MS (ESI): m/z487.2 [M+H]⁺.

Step 5. A mixture of compound 21-4 (180 mg, 0.371 mmol) and LiOH.H₂O (47mg, 1.1 mmol) in MeOH/THF/H₂O (2 mL/4 mL/1 mL) was stirred at 75° C. for30 min. The resulting mixture was acidified to pH 5-6 by adding 2 N aq.HCl. The suspension was filtered and the solid was dried in vacuo togive compound 21-5 (150 mg, 93% yield) as a white solid. LC-MS (ESI):m/z 459.1 [M+H]⁺.

Step 6. To a solution of compound 21-5 (150 mg, 0.327 mmol) in DMF (5mL) was added HATU (187 mg, 0.491 mmol). After stirring at rt for 30min, the mixture was added DIPEA (127 mg, 0.982 mmol) and MeNH₂.HCl (66mg, 0.98 mmol). Subsequently, the mixture was stirred at rt for 30 minand poured into ice-water (50 mL). The suspension was filtered and thesolid was purified by preparative HPLC to give compound 21-6 (32 mg, 21%yield) as a white solid. LC-MS (ESI): m/z 472.2 [M+H]⁺.

Synthesis of Compound 21-7. Following the same scheme and replacing(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate with its(R)-enantiomer, compound 21-7 was obtained. LC-MS (ESI): m/z 472.2[M+H]⁺. Long column (30 min) HPLC and Chiral HPLC showed there was onlyone diastereomer formed during the reductive-elimination step; however,the chirality of the benzylic carbon in compound 21-7 was notdetermined.

Step 1. Refer to Scheme 22. A solution of compound 6-5 (1.0 g, 2.28mmol) in DCM (200 mL) was cooled to −78° C. and O₃ was flushed throughuntil the starting material disappeared as monitored by TLC. ExcessiveO₃ was removed completely by flushing the reaction mixture with N₂.Subsequently, NaBH₄ (866 mg, 22.8 mmol) and MeOH (40 mL) were added tothe mixture. After stirring at −78° C. for 3 hrs, the reaction mixturewas warmed to rt and water (200 mL) was added. The aqueous phase wasextracted with DCM (50 mL×3) and the combined organic extracts werewashed with water (100 mL×2) and brine (50 mL) and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive compound 22-1 (958 mg, 94% yield) as a white solid. LC-MS (ESI):m/z 430.1 [M−H₂O]⁺.

Step 2. A mixture of compound 22-1 (1.0 g, 2.24 mmol) and TsOH.H₂O (170mg, 0.90 mmol) in toluene (40 mL) was refluxed overnight. The solventwas removed and the residue was purified by silica gel columnchromatography (Petroleum ether/Acetone=10/1) to give compound 22-2 (600mg, 63% yield) as a white solid. LC-MS (ESI): m/z 430.1 [M+H]⁺.

Step 3. A solution of Et₂Zn (1.1 M in hexane, 27.5 mL, 27.5 mmol) wasadded into DCM (30 mL) dropwise at −78° C. under an atmosphere of N₂,followed by addition of CH₂I₂ (4.4 mL, 55.0 mmol). After the reactionmixture was stirred at −78° C. for 30 min, a solution of compound 22-2(536 mg, 1.25 mmol) and TFA (0.5 mL) in DCM (10 mL) was added. Theresulting mixture was stirred at −78° C. for 3 hrs and then partitionedbetween water (80 mL) and DCM (80 mL). The aqueous phase was extractedwith DCM (50 mL×3). The combined organic extracts were washed with water(100 mL×3) and brine (50 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=10/1 (v/v)) to give compound 22-3(190 mg, 35% yield) as a yellow solid. LCMS (ESI): m/z 444.1 [M+H]⁺; ¹HNMR (500 MHz, CDCl₃): δ 8.11 (m, 1H), 8.02-8.04 (m, 2H), 7.53 (s, 1H),7.16-7.20 (m, 2H), 4.41-4.44 (m, 2H), 4.11 (m, 1H), 3.40 (m, 1H), 3.02(s, 3H), 2.28 (m, 1H), 2.18 (m, 2H), 1.42 (t, 3H), 1.20 (m, 2H), 0.63(m, 1H), 0.41 (m, 1H) ppm.

Step 4. To a solution of compound 22-3 (190 mg, 0.429 mmol) in MeOH/THE(5 mL/5 mL) was added 2 N aq. LiOH (0.857 mL, 1.761 mmol). The resultingmixture was stirred at 75° C. overnight, then cooled to rt, acidifiedwith 2 N aq. HCl to pH 5-6, and extracted with EtOAc (30 mL×2). Thecombined organic extracts were washed with H₂O (25 mL) and brine (25 mL)and dried with anhydrous Na₂SO₄. The solvent was removed and the residuewas dried in vacuo to give compound 22-4 (178 mg, 99% yield) as a whitesolid, which was used directly in the next step without furtherpurification. LC-MS (ESI): m/z 337.1 [M-Ms].

Step 5. To a solution of compound 22-4 (138 mg, 0.33 mmol) in DMF (3 mL)was added HATU (152 mg, 0.40 mmol) at rt. The resulting mixture wasstirred for 30 min and then added DIPEA (86 mg, 0.67 mmol) andCH₃NH₂.HCl (45 mg, 0.67 mmol). After stirring at rt for 20 min, thereaction mixture was poured into water and the suspension was filtered.The solid was washed with water, dried in vacuo, and re-crystallized inEtOAc and hexane to give compound 22-5 as white solid (120 mg, 84%yield). LC-MS (ESI): m/z 429.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO): δ 8.49(s, 1H), 7.94-7.97 (m, 2H), 7.63 (s, 1H), 7.57 (s, 1H), 7.39 (t, J=9.0Hz, 2H), 3.95-4.00 (m, 1H), 3.26-3.29 (m, 1H), 3.14 (s, 3H), 2.84 (d,J=4.5 Hz, 3H), 2.14-2.23 (m, 2H), 1.11-1.22 (m, 2H), 0.44-0.52 (m, 1H),0.30-0.33 (m, 1H) ppm. Compound 22-5 was separated to give a pair ofenantiomers: enantiomer 22-5_A (t_(R)=2.48 min) and enantiomer 22-5_B(t_(R)=4.90 min) detected by UV absorption at 214 nm on a 4.6 mm×250mm×5 μm Lux Amylose-2 column (column temperature: 40.2° C.; eluent:MeOH/liquid CO₂=40/60 (v/v); CO₂ flow rate: 1.8 g/min and co-solventflow rate: 1.2 g/min; front pressure: 207 bar and back pressure: 151bar).

Step 1. Refer to Scheme 23. A mixture of compound 15-6 (8.0 g, 16.7mmol) and 10% Pd/C (4.0 g) in EtOAc (200 mL) was stirred at rt for 3 hrsunder an atmosphere of H₂. The reaction mixture was filtered through aCelite® 545 pad and the filtered cake was washed with EtOAc (50 mL×2).The filtrate was concentrated and the residue was dried in vacuo to givecompound 23-1 (7.5 g, quantitative yield as a yellow solid. LC-MS (ESI):m/z 450.2 [M+H]⁺.

Step 2. To a solution of compound 23-1 (7.5 g, 16.7 mmol) in anhydrouspyridine (100 mL) was added dropwise a solution of MsCl (1.4 mL, 17.54mmol) in anhydrous DCM (20 mL) at 0° C. After stirring at 0° C. for 3hrs, the reaction mixture was diluted with EtOAc (500 mL). The resultingmixture was washed with 1 M aq. HCl (200 mL×3) and brine (100 mL×2) anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasre-crystallized in EtOAc to give compound 23-2 (7.9 g, 90% yield) as apale brown solid. LC-MS (ESI): m/z 528.1 [M+H]⁺.

Step 3. To a solution of compound 23-2 (7.9 g, 15.0 mmol) in DMF (150mL) was added K₂CO₃ (8.3 g, 60.0 mmol), followed by 5-bromo-1-pentene(2.68 g, 18.0 mmol). After stirring at 80° C. for 2 hrs, the reactionmixture was concentrated. The residue was diluted with EtOAc (200 mL)and water (200 mL). The aqueous phase was extracted with EtOAc (150mL×3). The combined organic extracts were washed with (250 mL) and brine(250 mL) and dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was dried in vacuo to give compound 23-3 (7.9 g, 93% yield)as a yellow solid. LC-MS (ESI): m/z 618.2 [M+Na]⁺.

Step 4. To a solution of compound 23-3 (7.6 g, 12.8 mmol) in DCM (100mL) was added dropwise BCl₃ in DCM (31.9 g, 31.9 mmol.) at −30° C. underan atmosphere of N₂. After stirring at −30° C. for 2 hrs, the reactionmixture was poured into ice-water (300 mL) and the resulting mixture wasextracted with DCM (150 mL×3). The combined organic extracts were washedwith water (100 mL×3) and brine (100 mL) and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive crude compound 23-4 (7.2 g, 98% yield) as a yellow solid. LC-MS(ESI): m/z 554.2 [M+H]⁺.

Step 5. To a solution of compound 23-4 (7.5 g, 13.6 mmol) in DCM (100mL) were added DIPEA (5.25 g, 40.7 mmol) and DMAP (165 mg, 1.4 mmol),followed by a solution of Tf₂O (5.0 g, 17.6 mmol) in DCM (25 mL) at 0°C. After stirring at rt overnight, the reaction mixture was diluted withDCM (300 mL) and water (300 mL). The aqueous phase was extracted withDCM (300 mL×2). The combined organic extracts were washed with water(250 mL×3) and brine (250 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/Acetone=20/1 (v/v)) to give compound23-5 (8.0 g, 90% yield) as a yellow solid. LC-MS (ESI): m/z 686.1[M+H]⁺.

Step 6. A mixture of compound 23-5 (8.0 g, 11.7 mmol), LiCl (539 mg,12.8 mmol), Et₃N (3.24 mL, 23.3 mmol), Pd(OAc)₂ (392 mg, 1.8 mmol), andPPh₃ (1.22 g, 4.7 mmol) in DMF (80 mL) was stirred at 120° C. for 2 hrsunder an atmosphere of Ar. Subsequently, the reaction mixture wasconcentrated and the residue was partitioned between water (200 mL) andEtOAc (200 mL). The aqueous phase was extracted with EtOAc (150 mL×3)and the combined organic extracts were washed with water (250 mL×3) andbrine (250 mL) and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was purified by silica gel column chromatography(Petroleum ether/Acetone=10/1 (v/v)) to give compound 23-6 (4.0 g, 64%yield) as a yellow solid. LC-MS (ESI): m/z 536.1 [M+H]⁺; ¹H NMR (500MHz, CDCl₃): δ 8.02-8.04 (m, 2H), 7.95 (s, 1H), 7.68 (s, 1H), 7.07-7.10(m, 4H), 7.03-7.05 (m, 2H), 5.30 (m, 1H), 5.20 (d, 1H), 4.40-4.44 (t,2H), 3.85 (m, 2H), 2.87 (s, 3H), 2.52 (m, 2H), 1.95 (m, 2H), 1.42 (t,J=5.5 Hz, 3H) ppm.

Synthesis of Compound 23-7. Following the same procedures ofhydrolyzation and methylamide formation as described in the synthesis ofcompounds 6-6 and 7-1, respectively, compound 23-7 was obtained. LC-MS(ESI): m/z 521.1 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 7.83 (dd, J₁=1.6 Hz,J₂=6.2 Hz, 2H), 7.75 (s, 1H), 7.65 (s, 1H), 7.02-7.10 (m, 6H), 5.86 (m,1H), 5.29 (s, 1H), 5.17 (d, J=1.8 Hz, 1H), 3.82 (m, 2H), 2.99 (d, J=5.7Hz, 3H), 2.85 (3, 3H), 2.47 (m, 2H), 1.93 (m, 2H) ppm.

Synthesis of Compound 23-8. Following the same procedure ofisomerization as described in the synthesis of compound 7-4, compound23-8 was obtained. LC-MS (ESI): m/z 521.1 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃): δ 7.81 (dd, J₁=1.8 Hz, J₂=5.9 Hz, 2H), 7.63 (s, 1H), 7.26 (s,1H), 70.3-7.10 (m, 6H), 6.04 (m, 1H), 5.85 (m, 1H), 4.15 (m 2H), 2.98(d, J=5.1 Hz, 3H), 2.76 (s, 3H), 2.20 (s, 3H), 2.17 (m, 2H) ppm.

Synthesis of Compound 23-9. Following the same procedure ofhydrogenation as described in the synthesis of compound 7-3, compound23-9 was obtained. LC-MS (ESI): m/z 523.2 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃): δ 7.82 (d, J=8.7 Hz, 2H), 7.72 (s, 1H), 7.54 (s, 1H), 7.03-7.10(m, 6H), 5.84 (m, 1H), 4.10 (m, 1H), 3.24 (m, 2H), 3.08 (s, 3H), 3.00(d, J=5.2 Hz, 3H), 1.92-2.02 (m, 4H), 1.46 (d, J=6.7 Hz, 3H) ppm.Compound 23-9 was separated into a pair of enantiomers: enantiomer23-9_A (t_(R)=3.82 min) and enantiomer 23-9_B (t_(R)=4.99 min) detectedby UV absorption at 214 nm on a ChiralPak® IB column (columntemperature: 40.3° C.; eluent: MeOH/liquid CO₂=30/70 (v/v); CO₂ flowrate: 2.1 g/min and co-solvent flow rate: 0.9 g/min; front backpressure: 152 bar).

Synthesis of Compound 23-10. Following the same procedure ofcyclopropanation as described in the synthesis of compound 6-7, followedby hydrolyzation and methyl amide formation, compound 23-10 wasobtained. LC-MS (ESI): m/z 535.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.82(dd, J=2.0 Hz, J₂=5.0 Hz, 2H), 7.79 (d, J=3.0 Hz, 1H), 7.52 (s, 1H),6.97-7.10 (m 6H), 5.84 (m, 1H), 3.58-3.71 (m, 2H), 3.15 (s, 3H), 3.00(d, J=4.5 Hz, 3H), 1.94 (m, 2H), 1.61 (m, 2H), 1.04 (m, 2H), 0.92 (m,2H) ppm.

Step 1. Refer to Scheme 24. Following the same procedure as described inthe synthesis of compound 22-1, compound 24-1 was obtained as a yellowsolid in 80% yield. LC-MS (ESI): m/z=540.1 [M+H]⁺.

Step 2. Following the same procedure as described in the synthesis ofcompound 22-2, compound 24-2 was obtained as a yellow solid in 57%yield. LC-MS (ESI): m/z=522.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ8.03-8.06 (m, 2H), 7.77 (s, 1H), 7.07-7.09 (m, 4H), 7.03-7.05 (m, 2H),6.63 (d, 1H), 6.01 (d, 1H), 4.41-4.45 (m, 2H), 3.85-3.91 (brs, 2H), 2.80(brs, 2H), 2.76 (s, 3H), 1.43 (t, J=7.0 Hz, 3H) ppm.

Synthesis of Compound 24-3. Following the same procedure as described inthe synthesis of compound 23-7, compound 24-3 was obtained as a whitesolid in 88% yield. LC-MS (ESI): m/z 507.1 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃): δ 7.84 (d, J=9.0 Hz, 2H), 7.77 (d, J=12.0 Hz, 2H), 7.04-7.10 (m,6H), 6.60 (d, J=12.5 Hz, 1H), 5.97-5.99 (m, 1H), 5.81 (br, 1H),3.26-3.29 (m, 1H), 3.89 (br, 2H), 2.99 (d, J=5.0 Hz, 3H), 2.78 (br, 2H),2.75 (s, 3H) ppm.

Synthesis of Compound 24-4. Following the same procedure as described inthe synthesis of compound 23-9, compound 24-4 was obtained as a whitesolid in 50% yield. LC-MS (ESI): m/z 509.1 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃): δ 7.84 (d, J=9.0 Hz, 2H), 7.69 (s, 1H), 7.57 (s, 1H), 7.03-7.11(m, 6H), 5.83 (br, 1H), 3.69 (br, 2H), 3.06 (s, 3H), 2.97-3.00 (m, 5H),1.92-1.94 (m, 2H), 1.74 (br, 2H) ppm.

Synthesis of Compound 24-5. Following the same procedure as describedfor the synthesis of compound 23-10, compound 24-5 was obtained. LC-MS(ESI): m/z 521.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.91 (s, 1H), 7.84(d, J=8.0 Hz, 2H), 7.50 (s, 1H), 7.05-7.11 (m, 6H), 5.84 (m, 1H), 4.10(dt, J₁=5.0 Hz, J₂=15.0 Hz, 1H), 3.39 (dd, J₁=5.0 Hz, J₂=13.0 Hz, 1H),3.00 (s and d, J=3.5 Hz, 6H), 2.25 (m, 1H), 2.14 (m, 1H), 1.15 (m, 2H),0.63 (m, 1H), 0.39 (m, 1H) ppm. Compound 24-5 was separated into a pairof enantiomers: enantiomer 24-5_A (t_(R)=7.237 min) and enantiomer24-5_B (t_(R)=10.044 min) detected by UV absorption at 214 nm on a 4.6mm×250 mm×5 μm ChiralPak® AS-H column (column temperature: 40° C.;eluent: n-Hexane/EtOH/DEA=70/30/0.1 (v/v/v); flow rate: 1.0 mL/min).

Step 1. Refer to Scheme 25. A mixture of compound 25-1 (600 mg, 3.8mmol), 4-pentyn-1-ol (620 mg, 7.4 mmol), CuI (141 mg, 0.74 mmol), Et₃N(1.57 g, 11.4 mmol), and Pd(dppf)Cl₂ (266 mg, 0.38 mmol) in DMF (30 mL)was stirred at rt overnight under an atmosphere of N₂. The solvent wasremoved and the residue was purified by silica gel column chromatography(Petroleum ether/Acetone=4/1 to 2/1 (v/v)) to give compound 25-2 (250mg, 32% yield) as a yellow oil. LC-MS: (ESI) m/z 207.1 [M+H]⁺.

Step 2. A mixture of compound 25-2 (250 mg, 1.2 mmol) and 10% Pd/C (150mg) in MeOH (20 mL) was stirred at rt overnight under an atmosphere ofH₂. The mixture was filtered through a Celite® 545 pad and the filteredcake was washed with MeOH (25 mL×2). The filtrate was concentrated andthe residue was dried in vacuo to give compound 25-3 (200 mg, 91% yield)as a yellow oil. LC-MS: (ESI) m/z 181.1 [M+H]⁺.

Step 3. To a solution of compound 25-3 (200 mg, 1.1 mmol) and Et₃N (0.90mL, 6.6 mmol) in DCM (10 mL) was added dropwise a solution of MsCl (376mg, 3.3 mmol) in DCM (5 mL) over 10 min at 0° C. After stirring at rtfor 1 hr, the reaction mixture was filtered through a Celite® 545 padand the filtered cake was washed with DCM (25 mL×2). The filtrate wasconcentrated and the residue was dried in vacuo to give crude compound25-4 (495 mg) as yellow solid, which was used for the next step withoutfurther purification. LC-MS: (ESI) m/z 415.1 [M+H]⁺.

Step 4. A mixture of compound 25-4 (495 mg, 1.1 mmol) and K₂CO₃ (607 mg,4.4 mmol) in DMF (10 mL) and H₂O (2 mL) was stirred at 80° C. overnight.The solvent was removed and the residue was purified by silica gelcolumn chromatography (Petroleum ether/Acetone=3/1 to 1/1 (v/v)) to givecompound 25-5 (100 mg, 37% yield, two steps from compound 25-3) as awhite oil. LC-MS (ESI): m/z 241.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ8.40 (s, 1H), 8.34-8.35 (d, J=5.0 Hz, 1H), 7.29-7.30 (d, J=5.0 Hz, 1H),3.52 (br, 2H), 3.06 (s, 3H), 2.81 (br, 2H), 1.63 (br, 2H), 1.50 (br,2H), 1.40 (br, 2H) ppm.

Synthesis of Compound 25-7. Following the same procedure as described inthe synthesis of compound 13-5 from 13-3, compound 25-7 was obtained asa yellow solid in 33% yield (two steps from 25-5). LC-MS: (ESI) m/z446.1 [M+H]⁺.

Synthesis of Compound 25-9. Following the same procedure as described inthe synthesis of compound 13-12 from 13-10, compound 25-9 was obtainedas a yellow solid in 62% yield (two steps from 25-7). LC-MS: (ESI) m/z431.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 8.44 (s, 1H), 8.23 (s, 1H),7.65-7.68 (m, 2H), 7.21-7.25 (m, 2H), 5.48 (br, 1H), 3.65 (br, 2H), 3.09(s, 3H), 2.95 (br, 2H), 2.85-2.86 (d, J=5.0 Hz, 3H), 1.54-1.65 (m, 6H)ppm.

Synthesis of Compound 25-10. Following the same procedure as describedin the synthesis of compound 19-5 from 19-2, compound 25-10 was obtainedas a white solid. LC-MS: (ESI) m/z 440.1 [M+H]⁺; ¹H NMR (500 MHz,d⁶-DMSO): δ 9.04 (s, 1H,), 7.70 (s, 2H), 7.69 (s, 3H), 7.59-7.62 (m,2H), 7.25 (t, J=8.5 Hz, 2H), 3.71 (br, 2H), 3.24 (s, 3H), 3.01 (br, 2H),1.70 (br, 6H) ppm.

Step 1. Refer to Scheme 26. To a solution of prop-2-yn-1-ol (2.24 g, 40mmol) in DME (80 mL) was added KOH (2.7 g, 48 mmol) at 0° C. Afterstirring at 0° C. for 30 min, the mixture was drop-wisely added asolution of TsCl (8.36 g, 44 mmol) in DME (40 mL) and the resultingmixture was stirred at 0° C. for 4 hrs. Subsequently, the reactionmixture was concentrated and the residue was added DCM (50 mL) and water(50 mL). The aqueous phase was extracted with DCM (100 mL×3) and thecombined organic extracts were washed with water (100 mL) and brine (100mL) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography to givecompound 26-1 (4.3 g, 51% yield) as a colorless oil. LC-MS (ESI): m/z211.0 [M+H]⁺.

Step 2. To a solution of compound 8-4 (712 mg, 1.7 mmol) in DMF (30 mL)was added K₂CO₃ (414 mg, 3 mmol) under an atmosphere of argon. Afterstirring at rt for 1 hr, the reaction mixture was added 26-1 (714 mg,3.4 mmol) and the resulting mixture was stirred at 60° C. for 2 hrs. Themixture was concentrated and the residue was partitioned between EtOAc(100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc(50 mL×3) and the combined organic extracts were washed with water (50mL×2) and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was dried in vacuo to give compound 26-2 (700 mg, 90% yield) asa yellow solid. LC-MS (ESI): m/z 458.1 [M+H]⁺.

Step 3. To a solution of compound 26-2 (685 mg, 1.5 mmol) in EtOH (20mL) was added NaBH₄ (114 mg, 3 mmol) in portions at 0° C. After stirringat 0° C. for 2 hrs, the reaction was quenched by adding several drops ofacetone. The mixture was concentrated and the residue was partitionedbetween EtOAc (25 mL) and water (25 mL). The aqueous phase was extractedwith EtOAc (25 mL×3) and the combined organic extracts were washed withbrined (25 mL) and dried with anhydrous Na₂SO₄. The solvent was removedand the residue was dried in vacuo to give compound 26-3 (640 mg, 93%yield) as a colorless oil. LC-MS (ESI): m/z 460.1 [M+H]⁺.

Step 4. To a solution of compound 26-3 (640 mg, 1.4 mmol) and DMAP (10mg, 0.075 mmol) in DCM (50 mL) was added Et₃N (0.83 mL, 6 mmol) at 0°C., followed by MsCl (0.5 mL, 3 mmol). After stirring at 0° C. for 2hrs, the reaction mixture was diluted with DCM (50 mL). The mixture waswashed with sat. aq. NH₄Cl (25 mL) and brine (25 mL) and dried withanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=2/1 (v/v)) togive compound 26-4 (450 mg, 95% yield) as a yellow solid. LC-MS (ESI):m/z 538.1 [M+H]⁺.

Step 5. To a solution of NaN₃ (390 mg, 6 mmol) in DMF (5 mL) at 65° C.was added compound 26-4 (322 mg, 0.6 mmol). After stirring at 65° C. for24 hrs, the reaction mixture was concentrated. The residue waspartitioned between EtOAc (25 mL0 and water (25 mL). The aqueous phasewas extracted with EtOAc (25 mL×3) and the combined organic extractswere washed with brine (50 mL) and dried with anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=2/1 (v/v)) to give compound 26-5(121 mg, 41% yield) as a yellow solid. LC-MS (ESI): m/z 485.1 [M+H]⁺.

Synthesis of Compound 26-7. Following the same procedure as described inthe synthesis of compound 25-9 from 25-7, compound 26-7 was obtained asa white solid in 43% yield (two steps from compound 26-5). LC-MS: (ESI)m/z 470.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.99 (s, 1H), 7.87-7.90 (m,2H), 7.70 (s, 1H), 7.51 (s, 1H), 7.22 (t, J=7.5 Hz, 2H), 6.21 (m, 1H),5.85 (br, 1H), 4.97 and 5.17 (AB, J_(AB)=16.0 Hz, 2H), 3.20 (s, 3H),3.01 (d, J=4.5 Hz, 3H), 2.14 (d, J=6.5 Hz, 3H) ppm.

Step 1. Refer to Scheme 26a. To a solution of compound 8-4 (4.6 g, 11mmol) in a mixed solvent of DCM (20 mL) and EtOH (60 mL) at 0° C. wasadded NaBH₄ (756 mg, 20 mmol) in small portions. After stirring at 0° C.for 2 hrs, the reaction mixture was slowly added H₂O (20 mL) and thenconcentrated. The residue was extracted with DCM (100 mL×3) and thecombined organic extracts were washed with water (50 mL×3) and brine (50mL) and dried over anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (PE/EtOAc=2/1(v/v)) to give compound 26a-1 (4.3 g, 92% yield) as a yellow solid.LC-MS (ESI): m/z 404.1 [M−H₂O+H]⁺.

Step 2. To a solution of compound 26a-1 (4.3 g, 10 mmol) in toluene (120mL) were added DPPA (4.3 mL, 20 mmol) and DBU (3 mL, 20 mmol). Thereaction mixture was stirred at 50° C. for 4 hrs. Subsequently, themixture was concentrated and the residue was purified by silica gelcolumn chromatography (PE/EtOAc=2/1 (v/v)) to give compound 26a-2 (4.0g, 85% yield) as a yellow solid. LC-MS (ESI): m/z 447.1 [M+H]⁺.

Step 3. To a solution of compound 26a-2 (3.95 g, 8.8 mmol) in DMF (50mL) was added K₂CO₃ (1.38 g, 10 mmol) and the mixture was stirred at rtfor 30 min. Next, a solution of compound 26-1 (2.52 g, 12 mmol) in 20 mLDMF was added. After stirring at rt overnight, the reaction mixture waspoured into H₂O (150 mL). The mixture was extracted with EtOAc (100mL×3) and the combined organic extracts were washed with water (100mL×3) and brine (50 mL) and dried over anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(PE/EtOAc=2/1 (v/v)) to give compound 26a-3 (3.3 g, 78% yield) as ayellow solid. LC-MS (ESI): m/z 485.1 [M+H]⁺.

Step 4. To a solution of compound 26a-3 (3 g, 6.2 mmol) in DMSO/H₂O (60mL/20 mL) were added Sodium Ascorbate (2.32 g, 9.3 mmol) and CuSO₄.5H₂O(1.55 g, 6.2 mmol). After stirring at rt overnight, the reaction mixturewas poured into H₂O (100 mL). The resulting mixture was extracted withEtOAc (100 mL×3) and the combined organic extracts were washed withwater (50 mL×3) and brine (50 mL) and dried over anhydrous Na₂SO₄. Thesolvent was removed and the residue was purified by silica gel columnchromatography (DCM/MeOH=40/1 (v/v)) to give compound 26-5 (2.1 g, 66%yield) as a yellow solid. LC-MS (ESI): m/z 485.1 [M+H]⁺.

Step 5. Following the same procedure as that for the preparation of 1-16described in Scheme 1 and replacing compound 1-14 with 26-5, compound26-7 (1.3 g, 67% yield) was obtained as a white solid. LC-MS (ESI): m/z470.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.53 (q, J=4.8 Hz, 1H), 8.04(s, 1H), 7.97-7.99 (m, 2H), 7.96 (s, 1H), 7.60 (s, 1H), 7.42 (t, J=8.5Hz, 2H), 6.34 (q, J=7.0 Hz, 1H), 5.39 and 4.72 (AB, J_(AB)=17.5 Hz, 2H),3.56 (s, 1H), 2.86 (d, J=4.5 Hz, 3H), 1.89 (d, J=7.5 Hz, 3H) ppm.Compound 26-7 was separated into a pair of enantiomers: enantiomer26-7_A (t_(R)=8.596 min) and enantiomer 26-7_B (t_(R)=11.887 min)detected by UV absorption at 214 nm on a 4.6 mm×250 mm×5 μm ChiralPak®AS column (column temperature: 40° C.; eluent:n-Hexane/EtOH/DEA=70/30/0.1 (v/v/v); flow rate: 1.0 mL/min).

Step 1. Refer to Scheme 26b. Following the same procedure as that forthe synthesis of compound 26-7 described in Scheme 26 and replacingcompound 26-5 with 8-4, compound 26b-1 was obtained. LC-MS (ESI): m/z405.1 [M+H]⁺.

Step 2. Following the same procedure as that for the synthesis ofcompound 26a-1 described in Scheme 26a and replacing compound 8-4 with26b-1, compound 26b-2 was obtained. LC-MS (ESI): m/z 407.1 [M+H]⁺.

Step 3. Following the same procedure as that for the synthesis ofcompound 26a-2 described in Scheme 26a and replacing compound 26a-1 with26b-2, compound 26b-3 was obtained as a yellow solid. LC-MS (ESI): m/z390.1 [M-N₃+H]⁺.

Step 4. To a solution of compound 26b-3 (43 mg, 0.1 mmol) in DMF (2 mL)was added K₂CO₃ (28 mg, 0.2 mmol) and the resulting mixture was stirredat rt for 30 min. Next, a solution of 2-bromoacetonitrile (24 mg, 0.2mmol) in 1 mL DMF was added. After stirring at rt for 4 hrs, the mixturewas poured into H₂O (20 mL). The mixture was extracted with EtOAc (20mL×3) and the combined organic extracts were washed with water (15 mL×3)and brine (10 mL) and dried over anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by silica gel column chromatography(PE/EtOAc=2/1 (v/v)) to give compound 26b-4 (42 mg, 89% yield) as ayellow solid. LC-MS (ESI): m/z 429.1 [M-N₃+H]⁺.

Step 5. To a solution of compound 26b-4 (24 mg, 0.05 mmol) in DMF (2 mL)was added NH₄Cl (26, 0.5 mmol). After being heated at 150° C. in amicrowave reactor for 8 hrs, the reaction mixture was cooled to rt andpoured into H₂O (30 mL). The suspension was extracted with EtOAc (20mL×3) and the combined organic extracts were washed with water (15 mL×3)and brine (10 mL×1) and dried over anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by preparative HPLC to givecompound 26b-5 (15 mg, 63% yield) as a yellow solid. LC-MS (ESI): m/z471.1 [M+H]⁺; ¹H NMR (500 MHz, CD₃OD): δ 7.95-7.97 (m, 2H), 7.93 (s,1H), 7.90 (s, 1H), 7.27 (t, J=9 Hz, 2H), 6.34 (q, J=7 Hz, 1H), 5.48 (m,1H), 5.07 (m, 1H), 3.50 (s, 3H), 2.97 (s, 3H), 2.08 (br s, 3H) ppm.

Step 1. Refer to Scheme 26c. To a solution of compound 8-2 (5.0 g, 13.5mmol) in EtOH (150 mL) was added NaBH₄ (921 mg, 24.3 mmol) at rt. Afterstirring at rt for 4 hrs, the reaction mixture was added several dropsof acetone and concentrated. The residue was diluted with water (20 mL)and EtOAc (100 mL). The organic layer was washed with water (25 mL×2)and brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated. Theresidue was purified by silica gel column chromatography (PE/EtOAc=2/1(v/v)) to give compound 26c-1 (4.3 g, 85% yield) as a yellow solid.LC-MS (ESI): m/z 356.2 [M−H₂O+H]⁺.

Step 2. To a solution of compound 26c-1 (1.0 g, 2.7 mmol) in DMF (20 mL)at 0° C. was added dropwise a solution of PBr₃ (0.78 mL, 8.1 mmol) inDMF (3 mL). After stirring at 0° C. for 10 min, the reaction mixture wasadded water (20 mL). The mixture was extracted with EtOAc (20 mL×3). Thecombined organic extracts were washed with brine (50 mL), dried overanhydrous Na₂SO₄, and concentrated. The residue was purified by silicagel column chromatography (PE/EtOAc=10/1 (v/v)) to give compound 26c-2(500 mg, 43% yield) as a yellow solid. LC-MS (ESI): m/z 356.1 [M-Br+H]⁺.

Step 3. To a solution of compound 26c-2 (1.0 g, 2.7 mmol) and1H-imidazole-2-carbaldehyde (220 mg, 2.3 mmol) in DMF (5 mL) was addedNa₂CO₃ (366 mg, 3.45 mmol). After stirring at 80° C. for 2 hrs, thereaction mixture was diluted with water (20 mL). The resulting mixturewas extracted with EtOAc (20 mL×3). The combined organic extracts werewashed with water (20 mL×2) and brine (20 mL), dried over anhydrousNa₂SO₄, and concentrated. The residue was purified by silica gel columnchromatography (PE/EtOAc=10/1 (v/v)) to give compound 26c-3 (300 mg, 58%yield) as a yellow solid. LC-MS (ESI): m/z 452.1 [M+H]⁺.

Step 4. To a solution of compound 26c-3 (300 mg, 0.67 mmol) in EtOAc (10mL) was added 10% Pd/C (150 mg), and the resulting mixture was stirredat rt for 12 hrs under an atmosphere of H₂. at the completion of thereaction, the reaction mixture was filtered through Celite®545 and thefiltered cake was washed with EtOAc (20 mL×2). The filtrate wasconcentrated and the residue was purified by silica gel columnchromatography (DCM/MeOH 50/1 (v/v)) to give compound 26c-4 (150 mg, 56%yield) as a yellow solid. LC-MS (ESI): m/z 406.1 [M+H]⁺.

Step 5. To a solution of compound 26c-4 (150 mg, 0.37 mmol) in DCM (3mL) was added Et₃N (0.1 mL, 0.74 mmol), followed by MsCl (43 μL, 0.56mmol). After stirring at rt for 2 hrs, the reaction mixture was dilutedwith DCM (35 mL) and washed with water (15 mL×2) and brine (15 mL),dried over anhydrous Na₂SO₄, and evaporated. The residue was purified bysilica gel column chromatography (DCM/MeOH=50/1 (v/v)) to give compound26c-5 (60 mg, 34% yield) as a yellow solid. LC-MS (ESI): m/z 484.1[M+H]⁺.

Step 6. Following the same procedure as that used for the preparation of1-16 described in Scheme 1 and replacing compound 1-14 with 26c-5,compound 26c-6 was obtained as a white solid. LC-MS (ESI): m/z 469.1[M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.92 (s, 1H), 7.83-7.86 (m, 2H), 7.64(s, 1H), 7.21 (t, J=8 Hz, 2H), 6.96 (d, J=11.5 Hz, 2H), 5.82 (d, J=4.5Hz, 1H), 5.67-5.68 (m, 1H), 5.05 (s, 2H), 3.21 (s, 3H), 2.98 (d, J=5.5Hz, 3H), 2.05 (d, J=7.5 Hz, 3H) ppm.

Step 1. Refer to Scheme 27. To a stirred solution of compound 15-11 (1.0g, 2.0 mmol) in DMF (25 mL) was added K₂CO₃ (1.1 g, 8.0 mmol) at rt,followed by 3-bromo-2-methylpropene (324 mg, 2.4 mmol). After stirringat 80° C. for 2 hrs, the reaction mixture was cooled to rt andpartitioned between water (60 mL) and EtOAc (50 mL). The aqueous layerwas extracted with EtOAc (40 mL×3). The combined organic extracts werewashed with water (60 mL×3) and brine (60×2 mL) and dried over anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (PE/EtOAc=10/1 (v/v)) to give compound 27-1a(760 mg, 67% yield) as a yellow solid. LC-MS (ESI): m/z 588.1 [M+Na]⁺.

Step 2. To a stirred solution of compound 27-1a (375 mg, 0.66 mmol) in amixed solvent of THF (6 mL) and MeOH (6 mL) was added NaBH₄ (75.5 mg,2.0 mmol) in portions at 0° C. After stirring at 0° C. for 2 hrs, thereaction was quenched by adding several drops of acetone and theresulting mixture was concentrated. The residue was partitioned withwater (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted withEtOAc (30 mL×3). Subsequently, the combined organic extracts were washedwith water (30 mL×3) and brine (10 mL) and dried over anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (PE/EtOAc=3/1 (v/v)) to give compound 27-2a (369mg, 98% yield) as a yellow solid. LC-MS (ESI): m/z 590.2 [M+Na]⁺.

Step 3. To a stirred solution of compound 27-2a (320 mg, 0.56 mmol) inDCM (20 mL) were added phenylselenophtalimide (255 mg, 0.85 mmol) and(±)-camphorsulfonic acid (26 mg, 0.11 mmol) at 0° C. After stirring atrt overnight, the reaction mixture was concentrated and the residue waspurified by silica gel column chromatography (PE/EtOAc=3/1 (v/v)) togive compound 27-3a (290 mg, 71% yield) as a white solid. LC-MS (ESI):m/z 746.1 [M+Na]⁺.

Step 4. To a stirred solution of compound 27-3a (320 mg, 0.44 mmol) in amixed solvent of CH₂Cl₂ (30 mL) and EtOH (50 mL) was added Raney nickel(160 mg). After refluxing for 2 hrs, the reaction mixture was filteredthrough a pad of Celite® 545 and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (PE/EtOAc=4/1(v/v)) to give compound 27-4a (120 mg, 48% yield) as a yellow solid.LC-MS (ESI): m/z 590.2 [M+Na]⁺.

Step 5. Following the same procedure as that for the preparation ofcompound 1-16 described in Scheme 1 and replacing compound 1-14 with27-4a, compound 27-5a was obtained as a white solid. LC-MS (ESI): m/z553.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.82-7.87 (m, 4H), 7.04-7.11(m, 6H), 5.80-5.85 (m, 1H), 5.15 (q, J=6.4 Hz, 1H), 4.14 (d, J=14.0 Hz,1H), 3.11 (s, 3H), 2.99 (d, J=5.0 Hz, 3H), 2.98 (d, J=14.0 Hz, 1H), 1.67(d, J=7.0 Hz, 3H), 1.53 (s, 3H), 1.14 (s, 3H) ppm. Compound 27-5a wasseparated into a pair of enantiomers: enantiomer 27-5a_A (t_(R)=3.93min) and enantiomer 27-5a_B (t_(R)=4.66 min) detected by UV absorptionat 214 nm on a 4.6 mm×250 mm×5 μm ChiralPak® IA column (columntemperature: 40.2° C.; eluent: MeOH (0.1% DEA)/liquid CO₂=30/70 (v/v);CO₂ flow rate: 2.1 g/min and co-solvent flow rate: 0.9 g/min; backpressure: 152 bar).

Synthesis of Compound 27-5b. Following the same procedure as that forthe synthesis of compound 27-5a described in Scheme 27 and replacingcompound 15-11 with 8-4, compound 27-5b was obtained as a white solid.LC-MS (ESI): m/z 461.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.91 (dd,J₁=3.5 Hz, J₂=6.2 Hz, 2H), 7.89 (s, 1H), 7.86 (s, 1H), 7.19 (t, J=8.5Hz, 2H), 5.80 (m, 1H), 5.15 (q, J=6.5 Hz, 1H), 4.14 (d, J=14.5 Hz, 1H),3.12 (s, 3H), 3.00 (d, J=5.5 Hz, 3H), 2.89 (d, J=14.5 Hz, 1H), 1.66 (d,J=6.5 Hz, 3H), 1.54 (s, 3H), 1.15 (s, 3H) ppm. Compound 27-5b wasseparated into a pair of enantiomers: enantiomer 27-5b_A (t_(R)=2.31min) and enantiomer 27-5b_B (t_(R)=3.38 min) detected by UV absorptionat 214 nm on a 4.6 mm×250 mm, 5 μm ChiralPak® AD-H column (columntemperature: 39.6° C.; eluent: MeOH/liquid CO₂=30/70 (v/v); CO₂ flowrate: 2.1 g/min and co-solvent flow rate: 0.9 g/min; back pressure: 151bar).

Synthesis of Compound 28-3a. Refer to Scheme 28. Following the sameprocedure as that for the preparation of compound 27-3a from 15-11described in Scheme 27 and replacing 3-bromo-2-methylpropene with allylbromide, compound 28-3a was obtained as a white solid. LC-MS (ESI): m/z732.1 [M+Na]⁺.

Synthesis of Compound 28-5a. Following the same procedure as that forthe preparation of compound 27-5a from 27-3a described in Scheme 27 andreplacing compound 27-3a with 28-3a, compound 28-5a was obtained as awhite solid. LC-MS (ESI): m/z 539.2 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.89 and 7.78 (s, s, 1H), 7.83 (dd, J₁=6.5 Hz, J₂=8.5 Hz, 2H), 7.61 and7.58 (br s, s, 1H), 7.04-7.12 (m, 6H), 5.83 (d, J=4.0 Hz, 1H), 5.18 and4.98 (dd, dd, J₁=13.5 Hz, J₂=6.5 Hz, 1H), 4.13-4.16 and 3.78-3.81 (m, m,2H), 3.15 and 3.12 (s, s, 3H), 3.12 and 2.85 (m, m, 1H), 3.00 (d, J=5.0Hz, 3H), 1.73 (t, J=6.5 Hz, 3H), 1.23 and 1.17 (d, d, J=6.5 Hz, 3H) ppm.Alternatively, compound 28-5a can be obtained using compound 28-7a asthe starting material described in Scheme 28.

Synthesis of Compound 28-5b. Following the same procedure as that forthe preparation of compound 28-5a described in Scheme 27 and replacingcompound 27-3a with 28-3b, compound 28-5b was obtained as a white solid.LC-MS (ESI): m/z 447.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.89-7.92 (m,2H), 7.87 (s, 1H), 7.59 (s, 1H), 7.20 (t, J=8.5 Hz, 2H), 5.78 (m, 1H),4.98 (m, 1H), 4.14 (m, 2H), 3.15 and 3.12 (s, s, 3H), 3.01 (d, J=4.5 Hz,3H), 2.83 (m, 1H), 1.73 and 1.71 (d, d, J=7.0 Hz, 3H), 1.23 and 1.18 (d,d, J=6.5 Hz, 3H) ppm. Alternatively, compound 28-5b can be obtainedusing compound 28-7b as the starting material described in Scheme 28.

Synthesis of Compound 28-6a. To a solution of compound 28-3a (2.1 g, 3.0mmol) in DCM (200 mL) was added m-CPBA (563 mg, 3.3 mmol) at 0° C. Afterstirring at 0° C. for 30 min, the reaction mixture was washed withsaturated aq. NaHCO₃ solution and water. The organic layer was driedover anhydrous Na₂SO₄ and concentrated to dryness to give crude compound28-6a as a red solid, which was used in the next step without furtherpurification. LC-MS (ESI): m/z 748.1 [M+Na]⁺.

Synthesis of Compound 28-7a. Compound 28-6a (375 mg, 0.52 mmol) wasdissolved in dry toluene (300 mL) and the resulting solution was addedDBU (4.2 mL, 28.1 mmol) at 0° C. After stirring at 100° C. for 45 minunder an atmosphere of N₂, the reaction mixture was concentrated and theresidue was purified by silica gel column chromatography (PE/EtOAc=5/1to 3/1 (v/v)) to give compound 28-7a (248 mg, 87% yield) as an off whitesolid. LC-MS (ESI): m/z 552.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.05(d, J=9.0 Hz, 2H), 8.00 (s, 1H), 7.79 (s, 1H), 7.31 (m, 2H), 7.21-7.23(m, 2H), 7.12 (d, J=9.0 Hz, 2H), 5.46 (q, J=6.0 Hz, 1H), 4.67 (d, J=14.0Hz, 1H), 4.46 (s, 1H), 4.40 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 4.20 (d,J=14.0 Hz, 1H), 3.24 (s, 3H), 1.72 (d, J=6.0 Hz, 3H), 1.36 (t, J=7.0 Hz,3H) ppm.

Synthesis of Compound 28-8a. Under an atmosphere of N₂, ZnEt₂ (1M inhexane, 7.40 mL, 7.40 mmol) was added to dry DCM (20 mL) at −78° C.,followed by CH₂I₂ (1.2 mL, 14.8 mmol) over 10 min. The resulting mixturewas stirred at −78° C. for 30 min and then at −10° C. for 30 min. Themixture was cooled to −78° C. and a solution of TFA (137 μL, 1.9 mmol)in DCM (1 mL) was added dropwise. After stirring at −78° C. for 30 min,the mixture was added dropwise a solution of compound 28-7a (340 mg,0.62 mmol) in DCM (2 mL) at −78° C. The resulting mixture was stirred at−78° C. for 10 min, 0° C. for 1 hr, and 25° C. for 4 hrs. Subsequently,saturated aq. NH₄Cl solution (10 mL) was added and the mixture wasconcentrated. The residue was extracted with DCM (20 mL×3). The combinedorganic extracts were washed with saturated aq. NaHCO₃ solution andwater and dried over anhydrous Na₂SO₄. The solvent was removed and theresidue was purified by silica gel column chromatography (PE/EtOAc=10/1to 4/1 (v/v)) to give compound 28-8a (230 mg, 66% yield) as a whitesolid. LC-MS (ESI): m/z 566.2 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ8.06-8.08 (m, 2H), 8.01 (s, 1H), 7.88 (s, 1H), 7.30-7.34 (m, 2H),7.21-7.24 (m, 2H), 7.12-7.14 (m, 2H), 5.09 (q, J=6.0 Hz, 1H), 4.36 (q,J=7.5 Hz, 2H), 3.69 (d, J=15.0 Hz, 1H), 3.57 (d, J=15.0 Hz, 1H), 3.32(s, 3H), 1.57 (d, J=6.0 Hz, 3H), 1.35 (t, J=7.5 Hz, 3H), 0.71-0.96 (m,4H) ppm.

Synthesis of Compound 28-9a. Following the same procedure as that forthe preparation of 1-16 described in Scheme 1 and replacing compound1-14 with 28-8a, compound 28-9a was obtained as a white solid. LC-MS(ESI): m/z 551.2 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.50 (d, J=4.5 Hz,1H), 7.92 (d, J=9 Hz, 2H), 7.83 (s, 1H), 7.56 (s, 1H), 7.28-7.32 (m,2H), 7.17-7.20 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 5.06 (dd, J₁=12.5 Hz,J₂=6.5 Hz, 1H), 3.67 (d, J=15.5 Hz, 1H), 3.56 (d, J=14.5 Hz, 1H), 3.31(s, 3H), 2.84 (d, J=4.5 Hz, 3H), 1.54 (d, J=6 Hz, 3H), 0.70-0.93 (m, 4H)ppm. Compound 28-9a was separated into a pair of enantiomers: enantiomer28-9a_A (t_(R)=4.13 min) and enantiomer 28-9a_B (t_(R)=5.05 min)detected by UV absorption at 214 nm on a 4.6 mm×250 mm×5 μm Regis(R,R)-Whelk-ol column (column temperature: 39.3° C.; eluent: MeOH/liquidCO₂=50/50 (v/v); CO₂ flow rate: 1.5 g/min and co-solvent flow rate: 1.5g/min; front pressure: 218 bar and back pressure: 152 bar).

Synthesis of Compound 28-9b. Following the same procedure as that forthe preparation of compound 28-9a described in Scheme 28 and replacingcompound 15-11 with 8-4, compound 28-9b was obtained as a white solid.LC-MS (ESI): m/z 459.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.53 (m,1H), 7.97 (dd, J₁=5.5 Hz, J₂=8.7 Hz, 2H), 7.85 (s, 1H), 7.58 (s, 1H),7.41 (t, J=8.5 Hz, 2H), 5.06 (q, J=6.5 Hz, 1H), 3.68 (d, J=14.5 Hz, 1H),3.57 (d, J=14.5 Hz, 1H), 3.32 (s, 3H), 2.84 (d, J=4.5 Hz, 3H), 1.54 (d,J=6.5 Hz, 3H), 0.93 (m, 1H), 0.84-0.86 (m, 2H), 0.70 (m, 1H) ppm.Compound 28-9b was separated into a pair of enantiomers: enantiomer28-9b_A (t_(R)=4.36 min) and enantiomer 28-9b_B (t_(R)=6.09 min)detected by UV absorption at 214 nm on a 4.6 mm×250 mm 5 μm ChiralPak®AD-H column (column temperature: 39.8° C.; eluent: MeOH/liquid CO₂=30/70(v/v); CO₂ flow rate: 2.1 g/min and co-solvent flow rate: 0.9 g/min;back pressure: 150 bar).

Synthesis of Compound 28-10a. To a solution of compound 28-7a (680 mg,1.2 mmol) in THF (10 mL) was added BH₃.THF (7.4 mL, 7.4 mmol) at 0° C.After stirring at rt for 3 hrs, the reaction mixture was added 3 N aq.NaOH (7 mL) at 0° C., followed by 30% aq. H₂O₂ (7 mL). The reactionmixture was stirred at rt overnight and the added iced water (30 mL).The mixture was extracted with EtOAc (25 mL×2). The combined organicextracts were washed with water (20 mL×2), dried over anhydrous Na₂SO₄,and concentrated. The residue was purified by silica gel columnchromatography (DCM/Acetone=50/1 (v/v)) to give compound 28-10a (560 mg,80% yield) as a white solid. LC-MS (ESI): m/z 592.2 [M+Na]⁺.

Synthesis of Compound 28-10b. Following the same procedure as that forthe preparation of compound 28-10a and replacing compound 28-7a with28-7b, compound 28-10b was obtained as a white solid. LC-MS (ESI): m/z500.1 [M+Na]⁺.

Synthesis of Compound 28-11a. Following the same procedure as that forthe preparation of compound 1-16 described in Scheme 1 and replacingcompound 1-14 with 28-10a, compound 28-11a was obtained as a whitesolid. LC-MS (ESI): m/z 555.2 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ8.42-8.50 (m, 1H), 7.90-7.93 (m, 2H), 7.82 and 7.77 (s, s, 1H), 7.56 and7.54 (s, s, 1H), 7.27-7.31 (m, 2H), 7.17-7.19 (m, 2H), 7.11 (d, J=8.5Hz, 2H), 5.17 and 4.88 (m, m, 1H), 4.78 (m, 1H), 4.18 and 3.99 (m, m,1H), 3.93 (m, 1H), 3.45 (m, 1H), 3.47 (m, 1H), 3.38 and 3.36 (s, s, 3H),2.84 (d, J=4.5 Hz, 3H), 2.83 (m, 1H), 1.62 and 1.60 (d, d, J=6.5 Hz, 3H)ppm.

Synthesis of Compound 28-11b. Following the same procedure as that forthe preparation of compound 28-11a described in Scheme 28 and replacingcompound 28-10a with 28-10b, compound 28-11b was obtained as a whitesolid. LC-MS (ESI): m/z 463.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.52(m, 1H), 7.95-7.98 (m, 2H), 7.83 and 7.79 (s, s, 1H), 7.58 and 7.57 (s,s, 1H), 7.40 (t, J=9.0 Hz, 2H), 4.88 (q, J=6.5 Hz, 1H), 4.78 (t, J=5.5Hz, 1H), 4.19 (d, J=15 Hz, 1H), 3.92 (m, 1H), 3.43-3.48 (m, 1H), 3.39(s, 3H), 3.26-3.31 (m, 1H), 2.84 (d, J=4.5 Hz, 3H), 2.83 (m, 1H), 1.62and 1.60 (d, d, J=6.0 Hz, 3H) ppm.

Synthesis of Compound 28-12a. To a solution of compound 28-10a (200 mg,0.35 mmol), DMAP (21 mg, 0.18 mmol) and Et₃N (0.15 mL, 1.1 mmol) inCH₂Cl₂ (5 mL) was added TsCl (100 mg, 0.53 mmol) at 0° C. After stirringat rt for 2 hrs, the reaction mixture was added ice water (10 mL) andDCM (25 mL). The organic layer was washed with saturated aq. NaHCO₃ (10mL×2), water (10 mL×2) and brine (10 mL), dried over anhydrous Na₂SO₄,and concentrated. The residue was purified by silica gel columnchromatography (PE/EtOAc=6/1 to 2/1 (v/v)) to give the tosylate as awhite solid (230 mg, 91% yield). LC-MS (ESI): m/z 746.2 [M+Na]⁺.Subsequently, a mixture of the tosylate (140 mg, 0.19 mmol), MeSO₂Na (59mg, 0.58 mmol) and KI (964 mg, 0.581 mmol) in DMF (2 mL) was stirred at120° C. for 2 hrs. The mixture was then poured into water (15 mL). Theresulting precipitate was filtered and the white was washed with water(15 mL×3) and dried in vacuo to give compound 28-12a (100 mg, 82%yield). LC-MS (ESI): m/z 654.1 [M+Na]⁺.

Synthesis of Compound 28-12b. Following the same procedure as that forthe preparation of compound 28-12a described in Scheme 28 and replacingcompound 28-10a with 28-10b, compound 28-12b was obtained as a whitesolid. LC-MS (ESI): m/z 562.1 [M+H]⁺.

Synthesis of Compound 28-13a. Following the same procedure as that forthe preparation of compound 1-16 described in Scheme 1 and replacingcompound 1-14 with 28-12a, compound 28-13a was obtained as a whitesolid. LC-MS (ESI): m/z 617.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ 7.94(s, 1H), 7.81 (dd, J₁=2.5 Hz, J₂=8.5 Hz, 2H), 7.61 (s, 1H), 7.05-7.13(m, 6H), 5.82 (m, 1H), 5.09 (q, J=8.5 Hz, 1H), 4.59 (t, J=11.5 Hz, 1H),4.24 (d, J=18.5 Hz, 1H), 3.16 (s, 3H), 3.05-3.13 (m, 3H), 3.07 (s, 3H),2.98 (d, J=6.0 Hz, 3H), 1.78 (d, J=8.5 Hz, 3H) ppm. Alternatively,compound 28-13a can be obtained using compound 28-11a as the startingmaterial as described in Scheme 28.

Synthesis of Compound 28-13b. Following the same procedure as that forthe preparation of compound 28-13a described in Scheme 28 and replacingcompound 28-12a with 28-12b, compound 28-13b was obtained as a whitesolid. LC-MS (ESI): m/z 525.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.52(m, 1H), 7.95-7.99 (m, 2H), 7.87 (s, 1H), 7.61 (s, 1H), 7.40 (t, J=8.5Hz, 2H), 4.98 (q, J=6.0 Hz, 1H), 4.39 (t, J=9.0 Hz, 1H), 4.20 (d, J=14.0Hz, 1H), 3.37 (s, 3H), 3.29-3.32 (m, 2H), 3.04 (s, 3H), 2.89 (m, 1H),2.85 (d, J=4.5 Hz, 3H), 1.66 (d, J=6.5 Hz, 3H) ppm. Alternatively,compound 28-13b can be obtained using compound 28-11b as the startingmaterial as described in Scheme 28.

Step 1. Refer to Scheme 29. To a solution of compound 4-2 (9.0 g, 18.9mmol) in DME (200 mL) and H₂O (400 mL) were added K₂CO₃ (7.8 g, 56.6mmol), Pd(dppf)Cl₂ (1.5 g, 1.9 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.4 g, 28.3 mmol).After stirring at 60° C. for 2 hrs under an atmosphere of Ar, thereaction mixture was concentrated and the residue was partitionedbetween water (150 mL) and EtOAc (150 mL). The aqueous phase wasextracted with EtOAc (100 mL×3) and the combined organic extracts werewashed with water (100 mL×3) and brine (100 mL) and dried over anhydrousNa₂SO₄. The solvent was removed and the residue was purified by silicagel column chromatography (PE/EtOAc=15/1 (v/v)) to give compound 29-1(5.0 g, 75% yield) as a yellow solid. LCMS (ESI): m/z 356.1 [M+H]⁺.

Step 2. To a solution of compound 29-1 (1.2 g, 3.4 mmol) in THF (50 mL),EtOH (20 mL) and HOAc (40 mL) was slowly added Zn (1.3 g, 20.1 mmol) at0° C. After stirring at rt for 2 hrs, the reaction mixture was filteredand the filtrate was concentrated. The residue was partitioned betweenwater (80 mL) and EtOAc (80 mL) and the organic layer was extracted withEtOAc (60 mL×3). The organic extracts were combined and washed withwater (80 mL×2), sat. aq. NaHCO₃ (80 mL) and brine (80 mL) and driedover anhydrous Na₂SO₄. The solvent was concentrated and the residue wasdried in vacuo to give crude compound 29-2 (1.0 g, 91% yield) as ayellow solid. LC-MS (ESI): m/z 326.1 [M+H]⁺.

Step 3. To a solution of compound 29-2 (1.0 g, 3.1 mmol) in anhydrouspyridine (5 mL) was treated with DMAP (20 mg), followed by a solution ofMsCl (1.1 g, 9.2 mmol) in DCM (3 mL) at 0° C. After stirring at rt for 3hrs, the reaction mixture was concentrated and the residue waspartitioned between water (20 mL) and EtOAc (20 mL). The aqueous layerwas extracted with DCM (30 mL×3) and the combined organic extracts werewashed with water (60 mL×2) and brine (60 mL) and dried over anhydrousNa₂SO₄. The solvent was removed and the residue was dried in vacuo togive crude compound 29-3 (1.1 g, 88% yield) as a yellow solid. LC-MS(ESI): m/z 404.1 [M+H]⁺.

Step 4. To a solution of compound 29-3 (700 mg, 1.7 mmol) in DMF (30 mL)were added K₂CO₃ (719 mg, 5.2 mmol) and KI (144 mg, 0.87 mmol), followedby 2-bromobenzyl chloride (534 mg, 2.6 mmol). After stirring at 70° C.for 3 hrs, the reaction mixture was concentrated and the residue waspartitioned between water (50 mL) and EtOAc (50 mL). The aqueous layerwas extracted with EtOAc (3×40 mL) and the combined organic extractswere washed with water (80 mL×3) and brine (50 mL) and dried overanhydrous Na₂SO₄. The solvent was removed and the residue was purifiedby silica gel column chromatography (Petroleum ether/EtOAc=15/1 (v/v))to give compound 29-4 (800 mg, 87% yield) as a yellow solid. LC-MS(ESI): m/z 574.0 [M+H]⁺.

Step 5. To a solution of compound 29-4 (770 mg, 1.34 mmol) in CH₃CN (25ml) were added Et₃N (4.6 mL), and Pd(PPh₃)₄ (1.55 g, 1.34 mmol). Afterstirring at 80° C. for several hours under an atmosphere of Ar, thereaction mixture was concentrated and the residue was purified by silicagel column chromatography (Petroleum ether/EtOAc=10/1 (v/v)) to givecompound 29-5 (260 mg, 40% yield) as a yellow solid. LC-MS (ESI): m/z492.1 [M+H]⁺.

Step 6. To a solution of compound 29-5 (150 mg, 0.31 mmol) in EtOH (30mL) was added 5% Pd/C (w/w, 200 mg). After stirring at 50° C. forseveral hours under an atmosphere of H₂, the reaction mixture wasfiltered through a pad of Celite®545. The filtered cake was washed withEtOH (15 mL×2). The filtrate was concentrated and the residue was driedin vacuo to give crude compound 29-6 (149 mg, 99% yield) as a yellowsolid. LC-MS (ESI): m/z 494.1 [M+H]⁺.

Step 7. Following the same procedure as that for the preparation ofcompound 1-16 described in Scheme 1 and replacing compound 1-14 with29-6, compound 29-7 was obtained (130 mg, 90% yield) as a pale brownsolid. LC-MS (ESI): m/z 479.1 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃): δ7.85-7.88 (m, 2H), 7.78 (s, 1H), 7.71 (s, 1H), 7.30 (d, 2H), 7.15-7.24(m, 5H), 5.76 (brs, 2H), 5.12 (d, J=16 Hz, 2H), 4.95 (d, J=16 Hz, 5H),4.57-4.62 (dd, J₁=15 Hz, J₂=7 Hz, 1H), 2.72 (d, J=5 Hz, 3H), 2.73 (s,3H), 1.80 (d, J=8 Hz, 3H) ppm. Compound 29-7 was separated into a pairof enantiomers: enantiomer 29-7_A (t_(R)=4.16 min) and enantiomer 29-7_B(t_(R)=6.05 min) detected by UV absorption at 214 nm on a 4.6 mm×250 mm5 μm ChiralPak® OD-H column (column temperature: 40.4° C.; eluent:MeOH/liquid CO₂=30/70 (v/v); CO₂ flow rate: 2.1 g/min and co-solventflow rate: 0.9 g/min; front pressure: 205 bar and back pressure: 148bar).

Chiral separation of Compound 8-5. Compound 8-5 (3.8 g) was separatedinto a pair of enantiomers: (R)-8-5 (t_(R)=2.61 min, 1.6 g, 84% yield)and (S)-8-5 (t_(R)=3.14 min, 1.6 g, 84% yield) detected by UV absorptionat 214 nm on a 4.6 mm×250 mm×5 μM ChiralPak® AD-H column (columntemperature: 40.2° C.; eluent: MeOH (0.1% DEA)/liquid CO₂=30/70 (v/v);CO₂ flow rate: 2.1 g/min and co-solvent flow rate: 0.9 g/min; frontpressure: 206 bar and back pressure: 149 bar).

Chiral Separation of Compound 15-12. Using the same prep-chiral HPLCcondition as that used for separating compound 8-5, Compound 15-12 (5.6g) was separated into a pair of enantiomers: (R)-15-12 (t_(R)=5.71 min,1.1 g, 39% yield) and (S)-15-12 (t_(R)=6.58 min, 1.0 g, 36% yield).

Synthesis of Compound 30-1a. To a solution of the enantiomer came outfirst from the chiral separation of compound 8-5 (t_(R)=2.61 min) (30mg, 0.07 mmol) and (R)-MαNP (18.4 mg, 0.08 mmol) in CH₂Cl₂ (2 mL) wasadded DCC (72.1 mg, 0.35 mmol), followed by DMAP (17.1 mg, 0.14 mmol).After stirring at rt for 20 hrs, the reaction mixture was concentratedand the residue was diluted with EtOAc (45 mL). The solution was washedwith water (20 mL) and brine (20 mL), dried with anhydrous Na₂SO₄, andconcentrated. The residue was purified by prep-HPLC to give compound30-1a (15 mg) as a white powder. LC-MS: (ESI)=656.2 [M+Na]⁺; ¹H NMR (500MHz, CDCl₃): δ 8.11-8.13 (m, 2H), 7.74-7.77 (m, 2H), 7.60 (d, J=7.0 Hz,2H), 7.47 (t, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.22 (t, J=9.0 Hz, 2H), 7.08(s, 1H), 7.00 (t, J=7.0 Hz, 1H), 6.76 (t, J=8.0 Hz, 1H), 6.07 (q, J=7.0Hz, 1H), 4.23-4.36 (m, 2H), 3.05 (s, 3H), 2.98 (s, 3H), 2.03 (s, 3H),1.49 (d, J=7.0 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H) ppm.

Synthesis of Compound 30-2a. Following the same procedure as that usedfor preparing compound 30-1a and replacing (R)-MαNP with (S)-MαNP,compound 30-2a was obtained. LC-MS: (ESI) m/z=656.2 [M+Na]⁺; ¹H NMR (500MHz, CDCl₃): δ 8.06-8.09 (m, 2H), 7.95 (d, J=8.5 Hz, 1H), 7.87 (s, 1H),7.82 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.67 (s,1H), 7.64 (d, J=7.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.28 (t, J=7.5 Hz,1H), 7.20 (t, J=7.5 Hz, 2H), 7.06 (t, J=7.5 Hz, 1H), 6.12 (q, J=6.5 Hz,1H), 4.35-4.41 (m, 2H), 3.12 (s, 3H), 3.00 (s, 3H), 2.00 (s, 3H), 1.48(d, J=6.5 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H) ppm.

Synthesis of Compound 30-1b. Following the same procedure as that usedfor preparing compound 30-1a and using the enantiomer came out firstfrom the chiral separation of compound 15-12 (t_(R)=5.71 min), compound30-1b was obtained. LC-MS: (ESI) m/z=748.2 [M+Na]⁺; ¹H NMR (500 MHz,CD₃Cl): δ 8.08-8.10 (m, 2H), 7.06-7.11 (m, 7H), 6.99 (t, J=7.0 Hz, 1H),6.75 (dt, J₁=1.0 Hz, J₂=8.0 Hz, 1H), 6.06 (q, J=7.0 Hz, 1H), 4.24-4.35(m, 2H), 3.05 (s, 3H), 2.98 (s, 3H), 2.03 (s, 3H), 1.49 (d, J=7.0 Hz,3H), 1.27 (t, J=7.0 Hz, 3H) ppm.

Synthesis of Compound 30-2b. Following the same procedure as that usedfor preparing compound 30-1b and replacing (R)-MαNP with (S)-MαNP,compound 30-2b was obtained. LC-MS: (ESI) m/z=748.2 [M+Na]⁺; ¹H NMR (500MHz, CD₃Cl): δ 8.06 (d, J=7.0 Hz, 2H), 7.93 (d, J=8.5 Hz, 1H), 7.85 (s,1H), 7.83 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.69 (s, 1H),7.63-7.66 (m, 2H), 7.46 (t, J=8.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H),7.04-7.10 (m, 7H), 6.10 (q, J=7.0 Hz, 1H), 4.36-4.39 (m, 2H), 3.13 (s,3H), 2.99 (s, 3H), 1.91 (s, 3H), 1.48 (d, J=7.0 Hz, 3H), 1.36 (t, J=7.0Hz, 3H) ppm.

Determination of Chirality. Refer to Scheme 31. Based on the generalrule of chemical shifts of a pair of diastereomeric esters derived froman alcohol with (R)-MαNP and (S)-MαNP, the chirality of the benzyliccarbon in the enantiomer came out first (t_(R)=2.61 min) from the chiralseparation of compound 8-5 was determined as R. Accordingly, thechirality of the benzylic carbon in the enantiomer came out first(t_(R)=5.71 min) from the chiral separation of compound 15-12 wasdetermined as R.

Synthesis of Compound (R)-8-5. Refer to scheme 32. A 25 mL flask wascharged with triethylamine (76 mg, 0.75 mmol, 7 eq.) in an ice bath,followed by adding formic acid (35 mg, 0.75 mmol, 7 eq.) dropwise. Afterstirring at rt for 20 min, a solution of compound 8-4 (45 mg, 0.107mmol, 1 equiv.) in DMF (6 mL) and RuCl[(R,R)-Tsdpen](p-cymene) (1.6 mg,0.0029 mmol 0.024 equiv.) were added. The resulting dark red reactionmixture was stirred at 40° C. overnight and then concentrated. Theresidue was purified by silica column chromatography (EtOAc/PE=1:1(v/v)) to give compound (R)-8-5 (30 mg, 66% yield, 95.5% ee) as a whitesolid. The absolute configuration of the sample (t_(R)=2.59 min) wasdetermined as R by taking chiral HPLC along with compound 8-5 followingchiral HPLC the condition in Scheme 30.

Synthesis of Compound (S)-8-5. Following the same procedure as describedfor the preparation of compound (R)-8-5 and replacingRuCl[(R,R)-Tsdpen](p-cymene) with RuCl[(S,S)-Tsdpen](p-cymene), compound(S)-8-5 (28 mg, 66% yield, 94.0% ee, t_(R)=3.12 min, S configuration)was obtained from compound 8-4 (42 mg, 0.1 mmol).

Synthesis of Compound (R)-15-12. Following the same procedure asdescribed for the preparation of compound (R)-8-5 and replacing compound8-4 with compound 15-11 (50 mg, 0.1 mmol), compound (S)-8-12 (38 mg, 75%yield, 95.9% ee, t_(R)=5.76 min, R configuration).

Synthesis of Compound (S)-15-12. Following the same procedure asdescribed for the preparation of compound (R)-15-12 and replacingRuCl[(R,R)-Tsdpen](p-cymene) with RuCl[(S,S)-Tsdpen](p-cymene), compound(S)-15-12 (70 mg, 70% yield, 96.6% ee, t_(R)=6.70 min, S configuration)was obtained from compound 15-11 (100 mg, 0.2 mmol).

Synthesis of Compound (R)-8-9. Using compound (R)-8-5 as the startingmaterial and following the same procedure for the preparation ofcompound 8-9 described in Scheme 8, compound (R)-8-9 was obtained.Chiral HPLC analysis determined that compound (R)-8-9 and enantiomer8-9_A obtained from chiral separation of compound 8-9 are identical.

Synthesis of Compound (R)-15-15. Using compound (R)-15-12 as thestarting material and following the same procedure for the preparationof compound 15-15 described in Scheme 15, compound (R)-15-15 wasobtained. Chiral HPLC analysis determined that compound (R)-15-15 andenantiomer 15-15_A obtained from chiral separation of compound 15-15 areidentical.

Syntheses of Diastereomers of Compounds 28-11a and -13a. Using eithercompounds (R)-15-12 or (S)-15-12 as the starting material and followingthe procedure for the preparation of compounds 28-11a and -13a describedin Scheme 28, those diastereomers of compounds 28-11a and -13a wereobtained, respectively. The absolute configurations of thosediastereomers were determined by 2D-COSY and NOESY spectra.

Syntheses of Diastereomers of Compounds 28-11b and -13b. Using eithercompounds (R)-8-5 or (S)-8-5 as the starting material and following theprocedure for the preparation of compounds 28-11b and -13b described inScheme 28, those diastereomers of compounds 28-11b

and -13b were obtained, respectively. The absolute configurations ofthose diastereomers were determined by 2D-COSY and NOESY spectra.

Step 1. Refer to Scheme 33. A mixture of compound 8-5 (500 mg, 1.2mmol), 2-chloro-1-(4-fluorophenyl)ethanone (266 mg, 1.5 mmol) and K₂CO₃(492 mg, 3.6 mmol) in DMF (4 mL) was stirred at 50° C. for 2 hrs.Subsequently, the reaction mixture was poured into water (100 mL) andthe suspension was filtered. The solid obtained was purified by silicagel column chromatography (PE/EtOAc=4/1 (v/v)) to give compound 33-1(500 mg, 76% yield) as a yellow solid. LC-MS (ESI): m/z 461.1[M−H₂O-Ms+H]⁺.

Step 2. To a solution of compound 33-1 (300 mg, 0.54 mmol) in THF/EtOH(5 mL/5 mL) was added NaBH₄ (102 mg, 2.7 mmol) at 0° C. After stirringat rt for 2 hrs, the reaction mixture was added several drops of acetoneand the concentrated. The residue was diluted with water (25 mL) andextracted with DCM (25 mL×3). The combined extracts were washed withwater (25 mL) and brine (25 mL), dried over anhydrous Na₂SO₄, andconcentrated. The residue was dried in vacuo to give compound 33-2 (300mg, 99% yield) as a yellow solid. LC-MS (ESI): m/z 463.2 [M−H₂O-Ms+H]⁺.

Step 3. To a solution of compound 33-2 (180 mg, 0.322 mmol) in CH₂Cl₂ (2mL) was added TMSOTf (143 mg, 0.64 mmol) at 0° C. After stirring at 0°C. for 10 min, the reaction mixture was added saturated aq. NaHCO₃ (25mL) and the resulting mixture was extracted with DCM (25 mL×2). Thecombined organic extracts were washed with water (25 mL) and brine (25mL), dried over anhydrous Na₂SO₄, and concentrated. The residue wasdried in vacuo to give compound 33-3 (160 mg, 92% yield) as a yellowsolid. LC-MS (ESI): m/z 564.0 [M+Na]⁺.

Step 4. Following the same procedure as that for the preparation ofcompound 1-16 described in Scheme 1 and replacing compound 1-14 with33-3, compound 33-4 was obtained (100 mg, 65% yield) as a white solid.LC-MS (ESI): m/z 527.1 [M+H]⁺; ¹H NMR (500 MHz, d⁶-DMSO): δ 8.50-8.56(m, 1H), 7.95-7.99 (m, 2H), 7.89 and 7.84 (s, s, 1H), 7.66 (m, 1H),7.32-7.42 (m, 4H), 7.16-7.21 (m, 2H), 5.35 and 5.08 (q, q, J=6.5 Hz,1H), 5.01 (d, J=10 Hz, 0.5 H), 4.20 (d, J=14 Hz, 0.5 Hz), 4.06 and 3.45(m, m, 1H), 3.46 and 3.44 (s, s, 3H), 3.28 and 2.99 (m, m, 1H),2.85-2.87 (m, 3H), 1.67-1.70 (m, 3H) ppm.

Step 1. Refer to Scheme 34. To a solution of (S)-15-12 (5.13 g, 10 mmol)in DMF (40 mL) was added K₂CO₃ (2.07 g, 15 mmol), the resulting mixturewas stirred at rt for 30 min. Subsequently, a solution of racemic2-(bromomethyl)oxirane (1.23 mL, 15 mmol) in DMF (10 mL) was dropwiseadded to the mixture. After stirring at 60° C. overnight, the reactionmixture was concentrated. The residue was diluted with H₂O (100 mL) andEtOAc (150 mL). The aqueous layer was extracted with EtOAc (150 mL×2).The combined organic extracts were combined, washed with H₂O (100 mL×2)and brine (100 mL), dried over anhydrous Na₂SO₄, filtrated andconcentrated. The residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=1/1 (v/v)) to give 34-1b (4.8 g,84% yield) as a white solid. LC-MS (ESI): m/z 570.1 [M+H]⁺.

Step 2. To a solution of TsOH (38 mg, 0.2 mmol) in toluene (4 mL) at100° C. was added 34-1b (57 mg, 0.1 mmol). After stirring at 100° C. for4 hr, the reaction mixture was concentrated and the residue wasdissolved in DCM (25 mL). The mixture was washed with sat. aq. NaHCO3(25 mL×2) abd Brine (25 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (Petroleum ether/EtOAc=1/1 (v/v)) to give a mixture of(S,S)-34-2b and (S,R)-34-2b (40 mg, 70% yield) as white solid with aratio of 7.5/1 determined by the integration of the benzylic carbon at5.08 ppm for (S,S)-34-2b and 5.20 ppm for (S,R)-34-2b, respectively.LC-MS (ESI): m/z 570.1 [M+H]⁺. (S,S)-34-2b ¹H NMR (500 MHz, CDCl₃): δ8.14 (s, 1H), 8.04 (m, 2H), 7.58 (s, 1H), 7.03-7.11 (m, 6H), 5.08 (q,J=6.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 4.13-4.19 (m, 2H), 3.73 (dd,J₁=3.5 Hz, J₂=11.5 Hz, 1H), 3.53 (dd, J₁=6.0 Hz, J₂=11.8 Hz, 1H), 3.18(s, 1H), 3.12 (m, 1H), 1.92 (bs, 1H), 1.77 (d, J=7.0 Hz, 3H), 1.44 (t,J=6.5 Hz, 3H) ppm. (S,R)-34-2b ¹H NMR (500 MHz, CDCl₃): δ 7.94-7.97 (m,3H), 7.52 (s, 1H), 6.96-7.03 (m, 6H), 5.20 (q, J=6.5 Hz, 1H), 4.35 (q,J=7.0 Hz, 2H), 3.94 (bm, 1H), 3.71 (dd, J₁=4.5 Hz, J₂=11.8 Hz, 1H),3.58-3.66 (m, 4H), 3.08 (s, 3H), 1.92 (bs, 1H), 1.67 (d, J=7.0 Hz, 3H),1.36 (t, J=7.0 Hz, 3H) ppm.

Comparison of the Stereo-Selectivity of the Acid CatalyzedEpoxide-Opening-Ring-Formation Step

Temperature and Starting material Acid Solvent reaction time(S,S)-34-2/(S,R)-34-2 ratio 34-1a TsOH (0.3 eq.) DCM 0° C., overnight1.0/3.0 34-1a TsOH (2.0 eq.) DCM rt, overnight 1.0/1.0 34-1a TsOH (2.0eq.) DCE 60° C., 4 hr 4.0/1.0 34-1b TsOH (0.3 eq.) DCM 0° C., overnight1.0/3.0 34-1b TsOH (2.0 eq.) DCM rt, overnight 1.0/1.0 34-1b TsOH (2.0eq.) DCE 60° C., 4 hr 6.5/1.0 34-1b TsOH (2.0 eq.) Toluene 100° C., 4 hr7.5/1.0 34-1b TsOH (2.0 eq.) DMF 150° C., 2 hr 3.0/2.0

Synthesis of (S,S)-35-1b. Refer to Scheme 35. To a solution of(S,S)-34-2b (120 mg, 0.22 mmol) and DMAP (159 mg, 1.3 mmol) in DCM (2mL) was added diphenyl phosphorochloridate (291 mg, 1.08 mmol) at 0° C.under an atmosphere of Ar. After stirring rt overnight, the reactionmixture was added ice water (10 mL) and DCM (10 mL). The organic layerwas washed with saturated aq. NaHCO₃ (10 mL×3) and water (10 mL×3),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue wasdried in vacuo to give crude (S,S)-35-1b (120 mg, 71% yield) as a whitesolid. LC-MS (ESI): m/z 787.2 [M+H]⁺.

Synthesis of (S,S)-35-2b. To a solution of (S,S)-35-1b (120 mg, 0.15mmol) in THF (5 mL) was added PtO₂ (50 mg). The resulting mixture wasflushed with H₂ and stirred at rt overnight. Subsequently, the mixturewas diluted with THF (25 mL) and filtered through Celite®545. Thefiltrate was concentrated and the residue was diluted with water (25mL). The suspension was filtered; the solid was washed with water (10mL) and CH₃CN (10 mL) and dried in vacuo to give (S,S)-35-2b (50 mg, 52%yield) as a white solid. LC-MS (ESI): m/z 635.2 [M+H]⁺. ¹H NMR (500 MHz,d⁶-DMSO): a 8.50 (d, J=4.5 Hz, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.81 (s,1H), 7.56 (s, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.15-7.18 (m, 2H), 7.10 (d,J=8.5 Hz, 2H), 4.89 (d, J=5.5 Hz, 1H), 4.10-4.16 (m, 1H), 4.03 (br, 1H),3.77 (br, 1H), 3.58-3.60 (m, 1H), 3.47 (br, 2H), 3.36 (s, 3H), 2.89 (br,1H), 2.83 (d, J=4.5 Hz, 3H), 1.60 (d, J=5.5 Hz, 3H) ppm.

Synthesis of (S,S)-35-3b. To a solution of N,N-dimethylglycine (45 mg,0.43 mmol), DCC (149 mg, 0.72 mmol) and (S,S)-34-2b (80 mg, 0.14 mmol)in CH₂Cl₂ (2 mL) was added DMAP (89 mg, 0.72 mmol) at rt. After stirringat rt overnight, the reaction mixture was filtered and the filtrated wasconcentrated. The residue was purified by preparative HPLC and productwas converted to its HCl salt to give (S,S)-35-3b (50 mg, 54% yield) aswhite solid. LC-MS (ESI): m/z 640.2 [M+H]. ¹H NMR (500 MHz, d⁶-DMSO): δ10.32 (br, 1H), 8.51 (d, J=5.0 Hz, 1H), 7.91 (d, J=9.0 Hz, 2H), 7.86 (s,1H), 7.57 (s, 1H), 7.30 (t, J=8.5 Hz, 2H), 7.17-7.20 (m, 2H), 7.12 (d,J=9.0 Hz, 2H), 4.92 (q, J=6.5 Hz, 1H), 4.19-4.26 (m, 6H), 3.04 (s, 1H),3.00 (br, 1H), 2.83 (s, 9H), 1.64 (d, J=6.0 Hz, 3H) ppm.

Synthesis of (S,S)-35-4c. To a solution of N-Boc-L-Alanine (68 mg, 0.36mmol), DCC (149 mg, 0.72 mmol) and (S,S)-35-1b (100 mg, 0.18 mmol) inCH₂Cl₂ (2 mL) was added DMAP (89 mg, 0.72 mmol) at rt. After stirring atrt overnight, the reaction mixture was filtered; the filtrate wasconcentrated and the residue was dried in vacuo to give crude(S,S)-35-4c (105 mg, 80% yield) as a white solid. LC-MS (ESI): m/z 626.1[M-Boc+2H]⁺.

Synthesis of (S,S)-35-5c. A mixture of (S,S)-35-3c (100 mg, 0.14 mmol)and HCl 4-dioxane (4.0 M, 3 mL) was stirred at rt for 2 hr. The solventwas removed and the residue was purified by prep-HPLC to give(S,S)-35-5c (50 mg, 58% yield) as a white solid. LC-MS (ESI): m/z 626.1[M+H]⁺. ¹H NMR (500 MHz, d⁶-DMSO): δ 8.48-8.51 (m, 1H), 8.40 (s, 2H),7.90 (d, J=8.5 Hz, 2H), 7.81 (s, 1H), 7.56 (s, 1H), 7.31 (t, J=8.5 Hz,2H), 7.16-7.20 (m, 2H), 7.12 (d, J=9.0 Hz, 2H), 4.91 (q, J=6.5 Hz, 1H),4.09-4.26 (m, 5H), 4.00 (s, 3H), 2.95 (br, 1H), 2.83 (d, J=6.5 Hz, 1H),1.61 (d, J=4.5 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H) ppm.

Synthesis of (S,S)-35-5d. Following the same procedure as that used forpreparing (S,S)-35-4c and replacing N-Boc-L-Alanine with N-Boc-L-Valine,(S,S)-35-5d was obtained as a white solid in 69% yield. LC-MS (ESI): m/z654.2 [M+H]⁺. ¹H NMR (500 MHz, d⁶-DMSO): δ 8.49-8.51 (m, 1H), 8.08 (br,2H), 7.91 (d, J=9.0 Hz, 2H), 7.86 (s, 1H), 7.57 (s, 1H), 7.30 (t, J=9.0Hz, 2H), 7.17-7.20 (m, 2H), 7.12 (d, J=9.0 Hz, 2H), 4.93 (d, J=6.5 Hz,1H), 4.15-4.20 (m, 4H), 3.87 (s, 1H), 3.36 (s, 3H), 2.95 (br, 1H), 2.84(d, J=4.0 Hz, 3H), 2.13-2.16 (m, 1H), 2.16 (d, J=6.5 Hz, 3H), 1.00 (d,J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H) ppm.

Biological Activity

Biological activity of the compounds of the invention was determinedusing an HCV replicon assay. The 1b_Huh-Luc/Neo-ET cell linepersistently expressing a bicistronic genotype 1b replicon in Huh 7cells was obtained from ReBLikon GMBH. This cell line was used to testcompound inhibition using luciferase enzyme activity readout as ameasurement of compound inhibition of replicon levels.

On Day 1 (the day after plating), each compound is added in triplicateto the cells. Plates incubated for 72 please use consistent terminologyprior to running the luciferase assay. Enzyme activity was measuredusing a Bright-Glo Kit (cat. number E2620) manufactured by PromegaCorporation. The following equation was used to generate a percentcontrol value for each compound.% Control=(Average Compound Value/Average Control)*100

The EC₅₀ value was determined using GraphPad Prism and the followingequation:Y=Bottom+(Top−Bottom)/(1+10^((Log IC50−X)*HillSlope))

EC₅₀ values of compounds are repeated several times in the repliconassay.

Compounds of the invention can inhibit multiple genotypes of HCVselected but not limited to 1a, 1b, 2a, 3a, and 4a. The EC₅₀s aremeasured in the corresponding replicon assays that are similar to HCV 1breplicon assay as described above.

Exemplary compounds of the disclosed invention are illustrated in theTables attached as Appendix A and Appendix B. Appendix A showsinhibitory activity of the compound with respect to HCV 1b, 1a, or 2aand HCV NS5B C316Y or S365A mutant as indicated. The biological activityagainst HCV 1b, 1a, or 2a is indicated as being *, **, ***, or ****,which corresponds to EC₅₀ ranges of EC₅₀>1000 nM, 100 nM<EC₅₀≦1000 nM,10 nM<EC₅₀≦100 nM, or EC₅₀≦10 nM, respectively. The biological activityagainst HCV NS5B C316Y or S365A mutant is indicated as being †, ††, or†††, which corresponds to EC₅₀ ranges of EC₅₀>1000 nM, 200 nM<EC₅₀≦1000nM, 200 nM≦EC₅₀, respectively.

Appendix A shows structures of 242 compounds of the invention identifiedby ID NOD B1-B242, and EC₅₀ values determined for 242 of the compounds.Of these, the 151 compounds with the highest measured activity can bedivided into two groups. Group 1 compound are those having a measuredEC₅₀ value, as determined by the concentration of the compound effectiveto produce a half-maximal inhibition of HCV 1b replication (EC₅₀) in a1b_Huh-Luc/Neo-ET cell line, in accordance with the method above, of 10nM or less. This group includes the compounds identified in Appendix Aby ID NOS: B5, B15, B20, B33, B35, B45, B67, B85, B92, B94, B107, B118,B120, B121, B127, B128, B130, B131, B132, B138, B139, B145, B148, B158,B163, B168, B169, B171, B187, B190, B191, B192, B196, B197, B198, B201,B207, B208, B212, B214, B218, B221, B226, B232, B233, B236, B237, B238,B239, and B240. Group 2 includes those compounds that have a measuredEC₅₀ of between 10 and 100 nM, and includes compounds identified inAppendix A by ID NOS: B2, B3, B4, B6, B7, B9, B16, B18, B19, B22, B29,B31, B32, B34, B36, B47, B48, B54, B55, B57, B60, B63, B71, B84, B93,B100, B101, B106, B108, B109, B111, B112, B113, B115, B116, B119, B123,B124, B134, B136, B137, B142, B144, B146, B147, B150, B151, B153, B154,B155, B156, B157, B159, B160, B161, B162, B164, B165, B166, B167, B170,B172, B173, B174, B175, B176, B178, B179, B180, B181, B183, B184, B186,B188, B189, B193, B195, B199, B200, B202, B203, B204, B205, B210, B215,B216, B217, B219, B220, B222, B223, B224, B225, B227, B228, B229, B230,B231, B234, B235, and B241.

Pharmaceutical Compositions

Another aspect of the invention provides a pharmaceutical compositioncomprising compounds of the invention. The compounds described hereincan be used as pharmaceutical compositions comprising the compounds,optionally together with one or more pharmaceutically acceptableexcipients or vehicles, and optionally other therapeutic and/orprophylactic ingredients. Such excipients are known to those of skill inthe art. Pharmaceutically acceptable salts can be used in thecompositions of the present invention and include, for example, mineralacid salts such as hydrochlorides, hydrobromides, phosphates, sulfatesand the like; and the salts of organic acids such as acetates,propionates, malonates, benzoates and the like. A thorough discussion ofpharmaceutically acceptable excipients and salts is available inRemington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: MackPublishing Company, 1990), and in Handbook of Pharmaceutical Excipients,6^(th) Edition, Ed. R. C. Rowe, P. J. Sheskey, and M. E. Quinn (AmericanPharmacists Association, 2009).

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, may include other pharmaceutical agents, adjuvants,diluents, buffers, etc.

The invention includes a pharmaceutical composition comprising acompound of the present invention including isomers, racemic ornon-racemic mixtures of isomers, or pharmaceutically acceptable salts orsolvates thereof together with one or more pharmaceutically acceptablecarriers and optionally other therapeutic and/or prophylacticingredients.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate and the like.

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule nonaqueous solution, suspension orsyrup. Tablets and capsules are preferred oral administration forms.Tablets and capsules for oral use will generally include one or morecommonly used carriers such as lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. Whenliquid suspensions are used, the active agent may be combined withemulsifying and suspending agents. If desired, flavoring, coloringand/or sweetening agents may be added as well. Other optional componentsfor incorporation into an oral formulation herein include, but are notlimited to, preservatives, suspending agents, thickening agents and thelike.

Another aspect of the invention provides use of the compounds of theinvention in the manufacture of a medicament.

In a first embodiment of the above aspect, the medicament is for thetreatment of hepatitis C.

Also provided is a method of treating hepatitis C comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of the invention, optionally in a pharmaceuticalcomposition. A pharmaceutically or therapeutically effective amount ofthe composition will be delivered to the subject. The precise effectiveamount will vary from subject to subject and will depend upon thespecies, age, the subject's size and health, the nature and extent ofthe condition being treated, recommendations of the treating physician,and the therapeutics or combination of therapeutics selected foradministration. Thus, the effective amount for a given situation can bedetermined by routine experimentation. The subject may be administeredas many doses as is required to reduce and/or alleviate the signs,symptoms or causes of the disorder in question, or bring about any otherdesired alteration of a biological system. One of ordinary skill in theart of treating such diseases will be able, without undueexperimentation and in reliance upon personal knowledge and thedisclosure of this application, to ascertain a therapeutically effectiveamount of the compounds of this invention for a given disease.

Combination Therapy

The compounds of the present invention and their isomeric forms andpharmaceutically acceptable salts thereof are useful in treating andpreventing HCV infection alone or when used in combination with othercompounds targeting viral or cellular elements or functions involved inthe HCV life cycle. Classes of compounds useful in the invention mayinclude, without limitation, all classes of HCV antivirals, bothdirect-acting and indirect-acting (‘cell-targeted’ inhibitors of HCVreplication). For combination therapies, mechanistic classes of agentsthat may be useful when combined with the compounds of the presentinvention include, for example, nucleoside and non-nucleoside inhibitorsof the HCV protease inhibitors, helicase inhibitors, NS5A inhibitors,NS4B inhibitors and medicinal agents that functionally inhibit theinternal ribosomal entry site (IRES), other NS5B inhibitors and othermedicaments that inhibit HCV cell attachment or virus entry, HCV RNAtranslation, HCV RNA transcription, replication or HCV maturation,assembly or virus release.

Specific compounds in these classes and useful in the invention include,but are not limited to, linear, macrocyclic, and heterocyclic HCVprotease inhibitors such as telaprevir (VX-950), boceprevir(SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC-435350(a.k.a. TMC-435), MK-7009, MK-5172, BI-201335, BMS-650032, ACH-1625,ACH-2784, ACH-1095 (HCV NS4A protease co-factor inhibitor), AVL-181,AVL-192, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, IDX-320, GS-9256,GS-9265, GS-9451, ABT-450, EP-013420 (and congeners) and VBY-376; thenucleosidic HCV polymerase (replicase) inhibitors useful in theinvention include, but are not limited to, R7128, PSI-7851, PSI-7977,PSI-938, PSI-879, PSI-6130, IDX-184, IDX-102, INX-189, R1479, R1626,UNX-08189, and various other nucleoside and nucleotide analogs and HCVinhibitors including, but not limited to, those derived from 2′-C-methylmodified nucleos(t)ides, 4′-aza modified nucleos(t)ides, and 7′-deazamodified nucleos(t)ides. NS5A inhibitors useful in the invention,include, but are not limited to, PPI-461, BMS-790052, BMS-824393,GS-5885, EDP-239, ACH-2928, AZD-7295, IDX-719, IDX-380, ABT-267,GSK-2336805, CF-102, A-831 and INTM-9916. Non-nucleosidic HCV polymerase(replicase) inhibitors useful in the invention, include, but are notlimited to, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333,ABT-072, PF-00868554 (filibuvir), BI-207127, GS-9190, A-837093,GSK-625433, JKT-109, GL-59728 and GL-60667. HCV NS5A inhibitors usefulin the present invention include, but are not limited to, PPI-461,EDP-239, BMS 790052 and BMS 824393, AZD7295, ACH-2928 and GS5885. HCV P7inhibitors useful in the present invention include BIT-225 and other P7inhibitors, as well as HCV NS4B inhibitors including but not limited tohistamine agents that antagonize HCV NS4B function.

In addition, NS5B inhibitors of the present invention may be used incombination with cyclophyllin and immunophyllin antagonists (eg, withoutlimitation, DEBIO compounds, NM-811, SCY-635, EP-CyP282, as well ascyclosporine and its derivatives), kinase inhibitors, inhibitors of heatshock proteins (e.g., HSP90 and HSP70), other immunomodulatory agentsthat may include, without limitation, interferons (-alpha, -beta,-omega, -gamma, -lambda or synthetic) such as Intron A™, Roferon-A™,Canferon-A300™, Advaferon™, Infergen™, Humoferon™, Sumiferon MP™,Alfaferone™, IFN-β™, Feron™ and the like; polyethylene glycolderivatized (pegylated) interferon compounds, such as PEGinterferon-α-2a (Pegasys™), PEG interferon-α-2b (PEGIntron™), pegylatedIFN-α-con1 and the like; long acting formulations and derivatizations ofinterferon compounds such as the albumin-fused interferon, Albuferon™,Locteron™ and the like; interferons with various types of controlleddelivery systems (e.g. ITCA-638, omega-interferon delivered by theDUROS™ subcutaneous delivery system); compounds that stimulate thesynthesis of interferon in cells, such as resiquimod and the like;interleukins; compounds that enhance the development of type 1 helper Tcell response, such as SCV-07 and the like; TOLL-like receptor agonistssuch as CpG-10101 (actilon), isotorabine, ANA773, SD-101, IMO-2125, andthe like; thymosin α-1; ANA-245 and ANA-246; histamine dihydrochloride;propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000;antibodies, such as civacir, XTL-6865 and the like and prophylactic andtherapeutic vaccines such as GI-5005, TG-4040, InnoVac C, HCV E1E2/MF59and the like. In addition, any of the above-described methods involvingadministering an NS5B inhibitor, a Type I interferon receptor agonist(e.g., an IFN-α) and a Type II interferon receptor agonist (e.g., anIFN-γ) can be augmented by administration of an effective amount of aTNF-α antagonist. Exemplary, non-limiting TNF-α antagonists that aresuitable for use in such combination therapies include ENBREL™,REMICADE™ and HUMTRA™.

NS5B inhibitors of the present invention may also be used withalternative forms of interferons and pegylated interferons, ribavirin orits analogs (e.g., tarabavarin, levoviron), microRNA, small interferingRNA compounds (e.g., SIRPLEX-140-N and the like) and microRNA agents(such as micro-RNA-122), nucleotide or nucleoside analogs, multifunctioninhibitors such as nitazoxanide, immunoglobulins, hepatoprotectants,anti-inflammatory agents and other direct and indirect inhibitors of HCVreplication. Inhibitors of other targets in the HCV life cycle includeNS3 helicase inhibitors; NS4A co-factor inhibitors; antisenseoligonucleotide inhibitors, such as ISIS-14803, ISIS-11, AVI-4065 andthe like; vector-encoded short hairpin RNA (shRNA); HCV specificribozymes such as heptazyme, RPI, 13919 and the like; entry inhibitorssuch as HepeX-C, HuMax-HepC and the like; alpha glucosidase inhibitorssuch as celgosivir, UT-231B and the like; KPE-02003002 and BIVN 401 andIMPDH inhibitors.

Other illustrative HCV inhibitor compounds include those disclosed inthe following publications: U.S. Pat. Nos. 5,807,876; 6,498,178;6,344,465; 6,054,472; 7,759,495; 7,704,992; 7,741,347; WO 02/04425; WO03/007945; WO 03/010141; WO 03/000254; WO 03/037895; WO 02/100851; WO02/100846; EP 1256628; WO 02/18369; WO 05/073216; WO 05/073195; WO08/021,927; US 20080050336; US 20080044379; US 2009004716; US20090043107; US 20090202478; US 20090068140; WO 10/096,302; US20100068176; WO 10/094,977; WO 07/138,242; WO 10/096,462; US 2010091413;WO 10/075,380; WO 10/062,821; WO 10/09677; WO 10/065,681 and WO10/065,668.

Additionally, combinations of, for example, ribavirin a NS3 proteaseinhibitor, a replicase inhibitor and interferon, may be administered asmultiple combination therapy with at least one of the compounds of thepresent invention. The present invention is not limited to theaforementioned classes or compounds and contemplates known and newcompounds and combinations of biologically active agents (see, forexample, Klebl et al. “Host cell targets in HCV therapy: novel strategyor proven practice, etc etc, each of which is incorporate by referencein their entirety herein). It is intended that combination therapies ofthe present invention include any chemically compatible combination of acompound of this inventive group with other compounds of the inventivegroup or other compounds outside of the inventive group, as long as thecombination does not eliminate the anti-viral activity of the compoundof this inventive group or the anti-viral activity of the pharmaceuticalcomposition itself.

Combination therapy can be sequential, that is treatment with one agentfirst and then a second agent (for example, where each treatmentcomprises a different compound of the invention or where one treatmentcomprises a compound of the invention and the other comprises one ormore biologically active agents) or it can be treatment with both agentsat the same time (concurrently). Sequential therapy can include areasonable time after the completion of the first therapy beforebeginning the second therapy. Treatment with both agents at the sametime can be in the same daily dose or in separate doses. The dosages forboth concurrent and sequential combination therapy will depend onabsorption, distribution, metabolism and excretion rates of thecomponents of the combination therapy as well as other factors known toone of skill in the art. Dosage values will also vary with the severityof the condition to be alleviated. It is to be further understood thatfor any particular subject, specific dosage regimens and schedules maybe adjusted over time according to the individual's need.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the invention as defined in the appended claims.

It is claimed:
 1. A compound having the structure:

wherein:

 is selected from the group consisting of

R¹ is selected from the group consisting of hydrogen, halide, —CF₃, —CN,—C(O)H, —C(O)OR⁶—, —C(O)NHR⁷, —C(O)N(OH)R⁷, —C(═NOMe)NHR⁷, C(═NOH)NHR⁷,—CH(CF₃)NHR⁸, —CH(CN)NHR⁹, —S(O)₂NHR¹⁰, —C(═NCN)NHR¹¹,

R² is substituted or unsubstituted aryl or heteroaryl; R⁶ is selectedfrom the group consisting of hydrogen, allyl, C₁₋₄ alkyl, cyclopropyl,and benzyl; R⁷ is selected from the group consisting of hydrogen, C₁₋₄alkyl, cyclopropyl, C₁₋₄ alkoxy, cyclopropoxy, alkylsulfonyl, andcycloalkylsulfonyl; R⁸, R⁹, R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, cyclopropyl, C₁₋₄alkoxy, and cyclopropoxy; and R¹⁷ is selected from the group consistingof H, F, Cl and CN; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein— R¹ is selected from the group consisting of

 and R² is selected from the group consisting of


3. The compound of claim 2, or a pharmaceutically acceptable saltthereof, selected from the group consisting of


4. A pharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable excipients or vehicles.
 5. A pharmaceuticalcomposition comprising the compound of claim 2, or a pharmaceuticallyacceptable salt thereof, together with one or more pharmaceuticallyacceptable excipients or vehicles.
 6. A pharmaceutical compositioncomprising the compound of claim 3, or a pharmaceutically acceptablesalt thereof, together with one or more pharmaceutically acceptableexcipients or vehicles.
 7. A method of treating HCV infection in asubject, comprising administering to the subject a pharmaceuticallyacceptable dose of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and continuing said administering until aselected reduction in the subject's HCV titer is achieved.
 8. A methodof treating HCV infection in a subject, comprising administering to thesubject a pharmaceutically acceptable dose of a compound of claim 2, ora pharmaceutically acceptable salt thereof, and continuing saidadministering until a selected reduction in the subject's HCV titer isachieved.
 9. A method of treating HCV infection in a subject, comprisingadministering to the subject a pharmaceutically acceptable dose of acompound of claim 3, or a pharmaceutically acceptable salt thereof, andcontinuing said administering until a selected reduction in thesubject's HCV titer is achieved.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is an aryl orheteroaryl having one or more R¹⁷ substituents.